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\DOI{10.5802/crchim.342}
\datereceived{2024-05-13}
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\datererevised{2024-09-12}
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\title{\textsc{l}-Tyrosine and \textsc{l}-DOPA: Promising scaffolds for the synthesis of
biologically active compounds}

\alttitle{\textsc{l}-Tyrosine et \textsc{l}-DOPA : Des \'{e}chafaudages mol\'{e}culaires
prometteurs pour la synth\`{e}se des compos\'{e}s biologiquement
actifs}

\author{\firstname{Euphrem} \lastname{Ndayiragije}\CDRorcid{0000-0003-4604-8053}}
\address{Department of Chemistry, Faculty of Science, University of
Mauritius, R\'{e}duit, Mauritius}
\address{Department of Chemistry, Faculty of Science, University of
Burundi, Bujumbura, Burundi}

\author{\firstname{Prakashanand} \lastname{Caumul}\CDRorcid{0000-0002-1819-2595}}
\addressSameAs{1}{Department of Chemistry, Faculty of Science,
University of Mauritius, R\'{e}duit, Mauritius}

\author{\firstname{Nausheen} \lastname{Joondan}\CDRorcid{0000-0002-1981-0332}}
\addressSameAs{1}{Department of Chemistry, Faculty of Science,
University of Mauritius, R\'{e}duit, Mauritius}

\author{\firstname{Minu~Gupta} \lastname{~Bhowon}\CDRorcid{0000-0003-1942-6098}\IsCorresp}
\addressSameAs{1}{Department of Chemistry, Faculty of Science,
University of Mauritius, R\'{e}duit, Mauritius}
\email[M. G. Bhowon]{mbhowon@uom.ac.mu}

\author{\firstname{Sabina} \lastname{Jhaumeer Laulloo}\CDRorcid{0000-0001-8841-9276}\IsCorresp}
\addressSameAs{1}{Department of Chemistry, Faculty of Science,
University of Mauritius, R\'{e}duit, Mauritius}
\email[S. Jhaumeer Laulloo]{sabina@uom.ac.mu}

\keywords{\kwd{\textsc{l}-Tyrosine}\kwd{\textsc{l}-DOPA}\kwd{Physicochemical
properties}\kwd{Biological activities}}

\altkeywords{\kwd{\textsc{l}-Tyrosine}\kwd{\textsc{l}-DOPA}\kwd{Propri\'{e}t\'{e}s
physico--chimiques}\kwd{Activit\'{e}s biologiques}}

\begin{abstract}
This review reports the synthetic strategies as well as the
physicochemical and biological properties of \textsc{l}-tyrosine and 
3,4-dihydroxyphenyl-\textsc{l}-alanine (\textsc{l}-DOPA)
esters, amides, and imine derivatives including dopamines and tyrosol
derivatives from 2010 to 2024. The variations in head
group and hydrophilic chain were found to influence the
physicochemical properties such as critical micelle concentration (CMC),
lipophilicity, and surface tension. The biological properties of
the previously reported \textsc{l}-tyrosine and \textsc{l}-DOPA derivatives such as
radical scavenging, antibacterial, antiproliferative, and anti-Parkinson
activities are also reported. 
\end{abstract}

\begin{altabstract}
Cette revue rapporte les strat\'{e}gies de synth\`{e}se ainsi que les
propri\'{e}t\'{e}s physico--chimiques et biologiques des esters, amides
et d\'{e}riv\'{e}s d'imines de la \textsc{l}-tyrosine et de la \textsc{l}-DOPA, y compris
les d\'{e}riv\'{e}s de la dopamine et du tyrosol, d\'{e}velopp\'{e}s
entre 2010 et 2024. Il a \'{e}t\'{e} constat\'{e} que la variation de
la t\^{e}te et de la cha\^{i}ne hydrophile influencent les
propri\'{e}t\'{e}s physico--chimiques telles que la concentration
micellaire critique (CMC), la lipophilie et la tension superficielle.
Les activit\'{e}s biologiques pr\'{e}c\'{e}demment rapport\'{e}es des
d\'{e}riv\'{e}s de la \textsc{l}-tyrosine et de la \textsc{l}-DOPA, tels que les effets
anti-radicalaires, anti-bact\'{e}riens, anti-prolif\'{e}ratifs et
anti-Parkinsonians, sont \'{e}galement rapport\'{e}es.
\end{altabstract}

\thanks{Higher Education Commission (HEC) of Mauritius through Mauritius Africa Scholarship Scheme 2021}

\shortrunauthors

\maketitle

{\vspace*{6pt}}

\twocolumngrid

\end{noXML}

\section{Introduction}

Aromatic amino acids are an important family of compounds that serve as
precursors for the synthesis of many biologically and neurologically
active compounds, essential for maintaining normal biological
functions. They have been used as building blocks for the synthesis of
a number of pharmaceutical compounds. Amino acid based surfactants
represent an important class of amphiphilic compounds bearing amino
acid residues such as the polar head group coupled to a hydrophobic
tail, which have found many applications in pharmaceutical as well as
cosmetic and detergent fields~\cite{1}. A number of surfactants derived
from phenylalanine and tyrosine have been found to possess interesting
physicochemical and biological properties, which are influenced by the
head group, chain length, as well as the hydrophilicity/lipophilicity
balance~\cite{2,3}. The tyrosine backbone can be identified in a number
of marketed drugs approved by the United States Food and Drug
Administration (FDA)~\cite{4,5,6} and has been recognized as a key
motif regulating the self-assembly and structural conformation of
proteins due to the presence of the phenolic group~\cite{7}. A crucial
role is played by 3,4-dihydroxyphenyl-\textsc{l}-alanine (\textsc{l}-DOPA)  in the
therapy of important neurodegenerative disorders such as Parkinson's
and Alzheimer's diseases~\cite{8,9}. In view of the growing interest in
these aromatic amino acids, the present review reports the synthetic
strategies and physicochemical as well as biological properties of
\textsc{l}-tyrosine and \textsc{l}-DOPA derivatives.

\section{Synthesis of \textsc{l}-tyrosine and \textsc{l}-DOPA derivatives}\label{sec1}

\textsc{l}-Tyrosine and \textsc{l}-DOPA are aromatic amino acids that consist of a
phenolic and a catechol moiety, respectively, and their derivatives
belong to a class of bioactive compounds with potential pharmaceutical
applications~\cite{10}. The presence of carboxylic, amino, and hydroxyl
groups allows the possibility of designing multiple structures
containing various functional groups such as esters, amides, imines,
and functional amines and alcohols (Figure~\ref{fig1}).{\vspace*{-.5pc}}

\begin{figure*}
\includegraphics{fig01}
\caption{\label{fig1}Various types of \textsc{l}-tyrosine and \textsc{l}-DOPA
derivatives.}
\end{figure*}

\subsection{Esters}\label{ssec11}

\textsc{l}-Tyrosine and \textsc{l}-DOPA ester derivatives are usually synthesized by
tethering the ${\upalpha}$-carboxylic or hydroxyl/phenolic groups. A
series of \textsc{l}-DOPA esters \textbf{1} have been reported where the
${\upalpha}$-carboxylic group was esterified by various aliphatic and
cyclic alcohols (Figure~\ref{fig2})~\cite{11}. The amino group moiety
can be further functionalized by protonation or alkylation, yielding
cationic ester derivatives. Joondan et~al.\ \cite{2,60} have reported a
number of \textsc{l}-tyrosine and \textsc{l}-DOPA alkyl ester hydrochlorides \textbf{2}
(Figure~\ref{fig2}) as well as their quaternary ammonium derivatives
\textbf{3}. The amino acid esters were synthesized by
esterification of \textsc{l}-tyrosine or \textsc{l}-DOPA with fatty alcohols in the
presence of \textit{para}-toluene sulfonic acid, followed by
reaction with HCl gas to convert the free amine moiety of the esters
into hydrochloride salts \textbf{2}. However, it was reported that the
reaction of the \textsc{l}-tyrosine and \textsc{l}-DOPA esters with bromoethane resulted
in ethylation of both the amino and the hydroxyl groups. Cleavage of
the \textit{O}-ethyl group with BBr\tsub{3} followed by quaternization
with methyl iodide gave diethylmethyl ester derivatives \textbf{3}
(Figure~\ref{fig2})~\cite{12}. Aluri and Jayakannan \cite{13}  reported the
monomeric tyrosine ester--urethane from \textsc{l}-tyrosine for which the amine
and carboxylic acid were converted into urethane and carboxylic ester
to form the C-methyl ester \textit{N}-methyl carbamate followed by
alkylation of the phenolic unit. Polycondensation with polyethylene
glycol (PEG) units resulted in tyrosine based poly(ester--urethane)s
\textbf{4} (Figure~\ref{fig2})~\cite{13}.{\vspace*{-.5pc}} 

\begin{figure*}
\includegraphics{fig02}
\caption{\label{fig2}\textsc{l}-Tyrosine and \textsc{l}-DOPA ester derivatives.}
\end{figure*}

\subsection{Amides}\label{ssec12}

\textsc{l}-Tyrosine and \textsc{l}-DOPA amide derivatives are generally prepared 
by functionalizing either the carboxylic or the amino group to give
\textit{N}-alkyl amide or \textit{N}-acyl derivatives, respectively
(Scheme~\ref{sch1}).

\begin{scheme*}
\includegraphics{sc01}
\caption{\label{sch1}General synthesis of \textsc{l}-tyrosine/\textsc{l}-DOPA amide
derivatives.}
\end{scheme*}

\subsubsection{\textit{N}-Alkyl amide} \label{sssec121}

The alkylation of the carboxylic moiety of \textsc{l}-tyrosine and \textsc{l}-DOPA
usually requires the use of protecting groups. Zhou et~al.\ \cite{15} and
Bhunia et~al.\ \cite{14} reported various DOPA alkyl amide derivatives
\textbf{5} and \textbf{6} where the amino and hydroxyl groups were
protected by di-\textit{tert}-butyl-dicarbonate (Boc) and benzyl
bromide, respectively. Hydrolysis of the \textit{N}- and
\textit{O}-protected \textsc{l}-DOPA methyl ester followed by coupling with
various amines and then deprotection and acylation gave \textsc{l}-DOPA alkyl amide
derivatives \textbf{5} and \textbf{6} (Scheme~\ref{sch2})~\cite{14,15}.

\begin{scheme*}
\includegraphics{sc02}
{\vspace*{4pt}}
\caption{\label{sch2}Synthesis of \textsc{l}-DOPA $N$-alkyl amide derivatives.}
{\vspace*{-9pt}}
\end{scheme*}

The \textit{O}- and \textit{N}-protected Boc-\textsc{l}-DOPA
\textit{tert}-butyldimethylsilyl was conjugated with the amino group of
lazabemide in the presence of [(1\textit{H}-benzotriazol-1yloxy)
tris(dimethylamino) phosphonium hexafluorophosphate] and
\textit{N}-methylmorpholine. Cleavage of \textit{O}-Bn and
\textit{N}-Boc moieties by using either trifluoroacetic acid or
hydrogen chloride gave \textsc{l}-DOPA lazabemide prodrug \textbf{7}
(Figure~\ref{fig3})~\cite{16}.

\begin{figure*}
\includegraphics{fig03}
\caption{\label{fig3}\textsc{l}-Tyrosine and \textsc{l}-DOPA closely related
\textit{N}-alkyl/aryl amide derivatives.}
\end{figure*}

Zhang et~al.\ \cite{17} reported the synthesis of tyrosine based hydroxamic
acid \textbf{8} via \textit{N}-Boc-protected tyrosine, followed by
coupling with phenylamine, and alkylation of the hydroxyl group with
methyl bromoacetate. \textit{N}-Deprotection followed successively by
acylation of the free amino group with 3-phenylpropionic acid and
treatment with NH\tsub{2}OK in methanol gave tyrosine based
hydroxamic acid \textbf{8} (Figure~\ref{fig3})~\cite{17}. 

\subsubsection{\textit{N}-Acyl amide} \label{sssec122}

\textit{N}-Acyl \textsc{l}-tyrosine or \textsc{l}-DOPA amide derivatives are obtained by
condensation of the amino group with fatty acids through an
\textit{N}-acyl linkage and, in most cases, no protecting groups were
employed. However, triethylamine (Et\tsub{3}N) in
combination with either other bases or coupling reagents has been used
for the \textit{N}-acylation. Triethylamine in the presence of
4-dimethyl-aminopyridine was employed for the condensation of
\textsc{l}-tyrosine or \textsc{l}-DOPA ester with fatty acid chlorides with different
chain lengths (C10--C18) to yield the corresponding \textit{N}-acyl
monomeric and gemini surfactants \textbf{9}--\textbf{11}
(Figure~\ref{fig4})~\cite{18,19}.

\begin{figure*}
{\vspace*{3pt}}
\includegraphics{fig04}
{\vspace*{3pt}}
\caption{\label{fig4}\textsc{l}-Tyrosine and \textsc{l}-DOPA \textit{N}-acyl amide
derivatives.}
{\vspace*{4pt}}
\end{figure*}

The coupling of \textsc{l}-DOPA methyl ester with the sulfurated compound
[2-methoxy-4-(3-thioxo-3\textit{H}-1,2-dithiol-5-yl)-phenoxy]acetic
acid gave \textsc{l}-DOPA amide \textbf{12} (Figure~\ref{fig4})~\cite{20}. To
promote the \textit{N}-acylation in the coupling reaction, Et\tsub{3}N
was used as the catalyst in the presence of coupling reagents, namely
\textit{N},\textit{N}$'$-dicyclohexyl carbodiimide (DCC) and
1-hydroxybenzotriazole (HOBt). Similar reaction conditions were used
for the coupling of diacetyl-\textsc{l}-DOPA-methyl ester hydrochloride with the
seleno-L-methionine derivative to give selenyl-\textsc{l}-DOPA derivative
\textbf{13} (Figure~\ref{fig4})~\cite{21}. Dimeric caffeic--\textsc{l}-DOPA
\textbf{14} (Figure~\ref{fig4}) was obtained by the coupling reaction
of the trifluoroacetate salt of dibenzyl \textsc{l}-DOPA methyl ester with
dimeric acid methyl caffeate, followed by deprotection of the catechol
units~\cite{22}. 

Desc\^{o}teaux et~al.\ \cite{23,24} reported the synthesis of
tyrosine--chlorambucil analogues \textbf{15a--c}, where \mbox{chlorambucil} is
linked to the tyrosine ${\upalpha}$-amine function by a spacer chain of
5 or 10 carbon atoms (Figure~\ref{fig4}). The coupling reaction of
\textsc{l}-tyrosine methyl ester hydrochloride or
\textit{m}-hydroxyphenyl--tyrosinamide with chlorambucil-6-aminohexanoic
or chlorambucil-11-amino-undecanoic acid at the ${\upalpha}$-amine
function gave tyrosine--chlorambucil methyl ester derivatives
\textbf{15a} and tyrosinamide--chlorambucil derivatives \textbf{15c}
(Figure~\ref{fig4}). Tyrosinol--chlorambucil derivatives \textbf{15b} 
(R ${=}$ CH\tsub{2}OH) were obtained from their corresponding
tyrosine--chlorambucil methyl esters \textbf{15a}  (R ${=}$\
CO\tsub{2}CH\tsub{3}) by treatment with LiBH\tsub{4}~\cite{23,24}. 

Tyrosine thiol derivatives \textbf{16} were obtained by the reaction of
thioester acid derivatives with \textit{O}- and \textit{N}-protected
tyrosine whereby the protecting groups di-\textit{tert}-butyl
dicarbonate (Boc\tsub{2}O) and benzyl bromide (BnBr) were used in
combination with the coupling reagents hexafluorophosphate
benzotriazole \mbox{tetramethyl} uranium (HBTU) and
di\textit{iso}propylethylamine (DIPEA). \textit{N}-Boc protection and
\textit{O}-benzylation of tyrosine, followed by concomitant methylation
and \textit{N}-Boc cleavage, gave benzyl ether tyrosine methyl ester
hydrochloride salt. Coupling thioester acid derivatives with benzyl
ether tyrosine methyl ester in the presence of HBTU and DIPEA followed
by hydrolysis in the presence of a sodium hydroxide solution provided
tyrosine based thiol derivatives \textbf{16}
(Figure~\ref{fig4})~\cite{25}.

\textsc{l}-DOPA phosphoramidate derivatives \textbf{17} (Scheme~\ref{sch3})
were obtained by the reaction of benzyl acetyl serinate or threoninate
with benzyl-protected \textsc{l}-DOPA in the presence of diphenylphosphite,
followed by the cleavage of the benzyl group by catalytic
hydrogenolysis~\cite{26}.

\begin{scheme*}
\includegraphics{sc03}
{\vspace*{5pt}}
\caption{\label{sch3}Synthesis of \textsc{l}-DOPA phosphoramidate with N--P
bond.}
{\vspace*{-6pt}}
\end{scheme*}

The syntheses of a series of ${\upalpha}$-methyl-\textsc{l}-DOPA urea
derivatives \textbf{18} (Scheme~\ref{sch4}) were reported by the
reaction of ${\upalpha}$-methyl-\textsc{l}-DOPA with various aryl isocyanates under
alkaline conditions~\cite{27}. 

\begin{scheme*}
\includegraphics{sc04}
{\vspace*{3pt}}
\caption{\label{sch4}Synthesis of ${\upalpha}$-methyl-\textsc{l}-DOPA urea
derivatives.}
{\vspace*{-9pt}}
\end{scheme*}

\subsubsection{\textit{N}-Heterocyclic amide} \label{sssec123}

\textit{N}-Heterocyclic moieties are present in various bioactive
molecules, and about 60\% of small-molecule drugs approved by the 
FDA in 2020 contain \textit{N}-heterocyclic
scaffolds with various ring sizes~\cite{28,29}. 

Giorgioni et~al.\ \cite{30} reported the synthesis of \textsc{l}-DOPA based
imidazolinones \textbf{19} via peptide formation by the coupling
reaction of \textit{O}-dibenzo-, \textit{N}-Boc-protected \textsc{l}-DOPA with
glycine methyl ester, followed by \textit{N}-Boc cleavage under acidic
conditions. Treatment of \textsc{l}-DOPA-glycyl methyl ester dipeptide with
either dimethylketone or diethylketone under alkaline conditions
followed by catalytic hydrogenation gave \textsc{l}-DOPA imidazolinones
\textbf{19}{\unskip\break} (Figure~\ref{fig5})~\cite{30}.

\begin{figure*}
{\vspace*{3pt}}
\includegraphics{fig05}
{\vspace*{3pt}}
\caption{\label{fig5}\textsc{l}-Tyrosine and \textsc{l}-DOPA \textit{N}-heterocyclic
amide.}
{\vspace*{3pt}}
\end{figure*}

The reported \textsc{l}-DOPA diketopiperazines \textbf{20} (Figure~\ref{fig5})
were synthesized by the coupling reaction of \textit{N}-Boc-methionine
or \textit{N}-Boc-cysteine derivatives with diaceto-DOPA methyl ester
hydrochloride in the presence of triethylamine and \textit{iso}butyl
chloroformate (IBCF) followed by deprotection and cyclization~\cite{31}.
Ravichandran et~al.\ \cite{32} reported the synthesis of
\textsc{l}-tyrosine derived hydantoin \textbf{21}, which was obtained by the
reaction of tyrosine with potassium cyanate in acidic medium. 

Treatment of \textsc{l}-tyrosine based hydantoin with methyl methacrylate
and 2-hydroxyethyl methacrylate in the presence of benzoyl peroxide
gave vinyl \textsc{l}-tyrosine based hydantoin \textbf{21}
(Figure~\ref{fig5})~\cite{32}. 

\subsubsection{Peptides}\label{sssec124}

\textsc{l}-Tyrosine or \textsc{l}-DOPA peptide derivatives consist of compounds
containing an \textsc{l}-tyrosine or an \textsc{l}-DOPA moiety linked to another amino
acid residue through a peptide bond. Peptides can be synthesized via
either a solid or a solution phase, and this strategy proceeds through
protection and deprotection of the amino or the carboxylic group.
Generally, in peptide synthesis, the use of coupling reagents such as
DCC, 1-ethyl-3-(3$'$-dimethyl-aminopropyl)carbodiimide (EDC), HOBt, and
IBCF is required. 

Pinnen et~al.\ \cite{33} reported \textsc{l}-DOPA tetrapeptide derivative
\textbf{22} (Figure~\ref{fig6}) synthesized in solution by an
elongation step using fluorenylmethoxycarbonyl (Fmoc) as the protecting
group. Deprotection of the \textit{N}-Fmoc-methionylglycyl
\textit{tert}-butyl ester using 1,8-diazabicyclo [5.4.0] undec-7-ene
and a coupling reaction of the deprotected dipeptide with
\textit{N}-acetyl glutamic acid methyl ester in the presence of DCC and
HOBt gave the tripeptide \textit{N}-acetyl methyl ester
glutamyl-methionylglycyl \textit{tert}-butyl ester. Removal of the
\textit{tert}-butyl ester group with trifluoroacetic acid 
followed by the coupling reaction of the tripeptide with diaceto-DOPA
methyl ester hydrochloride in the presence of Et\tsub{3}N and
IBCF gave \textsc{l}-DOPA tetrapeptide derivative
\textbf{22}~\cite{33}. The coupling reaction of \textsc{l}-DOPA esters with
\textit{N}-Boc-protected amino acids promoted by EDC and HOBt gave
protected dipeptide \mbox{derivatives,} which underwent deprotection by 4~M HCl
in dioxane solution to form  \textsc{l}-DOPA peptide derivatives
\textbf{23} (Figure~\ref{fig6})~\cite{34}. The natural amide bond
formation proceeds usually through protection and deprotection steps,
resulting in low yield. An alternative route of the synthesis of
peptides with O--C and N--C covalent bonds between amino acid residues,
involving Michael-like 1, 4 nucleophilic addition, has been reported by
Bizzarri et~al.\ \cite{35}. \textit{Ortho}-hydroxylation of 
\textit{N}-Boc-Tyr-OMe using 2-iodoxybenzoic acid for oxidative
functionalization and reaction with different \textit{N}-Boc-protected
amino acids yielded \textsc{l}-DOPA dipeptides \textbf{24} and \textbf{25}
(Figure~\ref{fig6}) via the reactive DOPA quinone\break
intermediate~\cite{35}.

\begin{figure*}
\includegraphics{fig06}
\caption{\label{fig6}\textsc{l}-DOPA peptide derivatives.}
\end{figure*}

\subsection{Imines} \label{ssec13}

Schiff bases (CH${=}$N) are found to be versatile pharmacophores for the
design and development of various bioactive compounds~\cite{36,37}. The
synthesis of \textsc{l}-tyrosine and \textsc{l}-DOPA Schiff bases \textbf{26}
(Figure~\ref{fig7}) was carried out by the condensation of
\textit{o}-vanillin with \textsc{l}-tyrosine or \textsc{l}-DOPA~\cite{38}. Ndayiragije
et~al.\ \cite{39} reported the synthesis of \textsc{l}-tyrosine and \textsc{l}-DOPA methyl
ester imine derivatives \textbf{27} and \textbf{28} (Figure~\ref{fig7})
by condensation of \textsc{l}-tyrosine and \textsc{l}-DOPA methyl esters with
2-hydroxy-1-naphthaldehyde and
\mbox{3-\textit{tert}-butyl-2-hydroxybenzaldehyde} in the presence of
triethylamine~\cite{39}. Similarly, the condensation of \textsc{l}-tyrosine with
2-hydroxy-1-naphthaldehyde,  methyldopa with
4-dimethylamino-benzaldehyde, and tyrosine with
acetylaceto-4-imino-antipyrine in the presence of piperidine yielded
imine derivatives \textbf{29}~\cite{40}, \textbf{30}~\cite{41}, and
\textbf{31} (Figure~\ref{fig7})~\cite{42}, respectively. 

\begin{figure*}
\includegraphics{fig07}
\caption{\label{fig7}\textsc{l}-Tyrosine and \textsc{l}-DOPA Schiff bases.}
\end{figure*}

\subsection{Dopamines}\label{ssec14}

Dopamine is a catecholamine and a neurotransmitter obtained by
decarboxylation of \textsc{l}-DOPA~\cite{43}. Dopamine plays important roles in
the brain and has also been used to prepare numerous drugs~\cite{44}.
The condensation of 3,4-dimethoxydopamine with cyanuric chloride
followed by deprotection of the catechol unit by using BBr\tsub{3} gave
hexadentate tris(dopamine) \textbf{32}
(Figure~\ref{fig8})~\cite{45}. Condensation of dopamine hydrochloride
with 4-hydroxycoumarin or isatin gave dopamine derivatives
\textbf{33} and \textbf{34}~\cite{46} while derivative
\textbf{35}~\cite{47} was obtained upon treatment of dopamine
hydrochloride with salicylaldehyde (Figure~\ref{fig8}). 

\begin{figure*}
\includegraphics{fig08}
\caption{\label{fig8}Dopamine derivatives.}
\end{figure*}

Thakur et~al.\ \cite{44} reported the synthesis of dopamine ester
derivative \textbf{36} (Figure~\ref{fig8}) by the PEGylation process,
where the two hydroxyl groups of dopamine were converted to the ester
derivative by condensation with ethylene glycol diacid in the presence
of H\tsub{2}SO\tsub{4}~\cite{44}. 

\subsection{Tyrosols}\label{ssec15}

Tyrosols are bioactive compounds and are well known as monophenolic
antioxidant compounds. The reduction of tyrosine methyl ester by
lithium borohydride (LiBH\tsub{4})~\cite{24} gave tyrosinol, which after
deamination formed tyrosol. Acylation at the primary hydroxyl group or
regioselective hydroxylation generates tyrosol esters or hydroxytyrosol
esters. Tyrosyl/hydroxytyrosol fatty acid esters \textbf{37} and
\textbf{38} were obtained by esterification of tyrosol or
hydroxytyrosol with fatty acids in the presence of Novozym 435
biocatalyst (Figure~\ref{fig9})~\cite{48,49,50,51}. 
Hydroxytyrosol--lipoic acid ester derivative \textbf{39}
(Figure~\ref{fig9}) was synthesized using an oxidative--reductive
process of the esterified tyrosol derivatives using 2-iodoxybenzoic
acid followed by in~situ reduction with sodium
dithionite (Na\tsub{2}S\tsub{2}O\tsub{4})
(Figure~\ref{fig9})~\cite{52}. 

\begin{figure*}
{\vspace*{-2pt}}
\includegraphics{fig09}
{\vspace*{-2pt}}
\caption{\label{fig9}Tyrosol derivatives.}
{\vspace*{-2pt}}
\end{figure*}

\section{Biological activities of \textsc{l}-tyrosine and \textsc{l}-DOPA
derivatives}\label{sec2}

\textsc{l}-Tyrosine and \textsc{l}-DOPA derivatives exhibit a wide range of biological
activities due to the presence of phenolic and catechol moieties,
respectively. The following sections review the biological properties
of \textsc{l}-tyrosine and \textsc{l}-DOPA derivatives in terms of radical scavenging,
antibacterial, antiproliferative, and bovine serum
albumin (BSA) binding activities. 

\subsection{Radical scavenging abilities}\label{ssec21}

Reactive oxygen species (ROS) are produced naturally in the human body
during  metabolic processes and are required for cellular
activities. The generation and inactivation of these ROS are balanced
by the natural antioxidants present in the organism~\cite{53}. In case
of unbalanced biochemical disorders, oxidative stress is activated by
the formation of surplus amount of ROS produced in~vivo, and
this leads to neuronal damage and cell death~\cite{27}. Antioxidants
act as scavengers of the ROS by inhibiting the initiation or
propagation of oxidizing chain reactions by  donating either hydrogen
atoms or electrons to the radicals~\cite{54}. 

In the literature, various methods have been used to evaluate the
potential of different antioxidants: 1,1-diphenyl-2-picrylhydrazyl
(DPPH) and 2,2$'$-azino-bis-3ethylbenzo-thiazoline-6-sulfonic~acid
(ABTS) represent the two most common antioxidants assays used.
Reactions with DPPH and ABTS are based on the process of hydrogen atom
transfer or electron transfer,  where the free radical on the
nitrogen atom in DPPH$^{\bullet}$ and the cationic chromophore
2,2-azinobis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS$^{\bullet+}$)
are reduced by receiving either a hydrogen atom or an electron from the
free radical scavenger~\cite{55,56}. 

Phenolic compounds are known to exhibit strong antioxidant properties
in biological systems and protect the human body against
neurodegenerative diseases as they donate hydrogen atoms to free
radicals. In \textit{ortho}-diphenolic compounds, the intramolecular
H-bonding weakens the O--H bond, leading to a lower O--H bond
dissociation enthalpy (77.7--80.1 kcal/mol) as compared to phenol
(85.1--88.0 kcal/mol), which is responsible for enhancing the radical
scavenging abilities~\cite{49}. Hence, \textsc{l}-DOPA derivatives containing
the catechol moiety exhibit higher activity over their corresponding
\textsc{l}-tyrosine derivatives.

The poor lipid solubility of the phenolic compounds limits their use in
biological systems. The lipophilicity of these compounds can be
improved by introducing alkyl chains through esterification or
etherification reactions without changing the reacting site responsible
for the antioxidant properties~\cite{49}. One study has shown that the
antioxidant activity of phenolic compounds can be improved by
lengthening the alkyl substituent attached to the phenolic compounds
due to the enhanced stabilization of the phenoxy radical resulting from
the electron-donating substituent~\cite{57}. Giorgioni et~al.\ \cite{30} 
reported that  ethyl DOPA imidazolinone \textbf{19b} ($\log P =
0.94$) exhibited higher radical scavenging abilities over its methyl
analogue \textbf{19a} ($\log P = 0.10$). The acylated hydroxytyrosyl
ester derivatives were also found to be better radical scavengers than
the free hydroxytyrosol~\cite{58}. Similar observations were made by
Sellami et~al.\ \cite{59}, where the acylated dopamine derivatives showed
higher ABTS radical scavenging abilities than dopamine~\cite{59}. Other
researchers revealed a parabolic trend with optimum activity for medium
alkyl chain length~\cite{49,60,61,62}, indicating a cut-off effect
normally observed between C8 and C14 alkyl chain lengths. Tofani et~al.\ 
\cite{62} observed that antioxidant capacity of the alkylated
hydroxytyrosol (C6--C10) increases as the alkyl chain increases,
with a threshold for the decyl chain, after which further chain
extension leads to similar activity, whereas in~vivo a drastic
decrease in antioxidant capacity was observed. \textsc{l}-DOPA fatty esters
\textbf{2} were found to follow a similar trend with a cut-off effect
for the C12 alkyl chain length, with a 
DPPH IC\tsub{50} value of 2.08~${\upmu}$g/mL and an
ABTS
IC\tsub{50} value of 21.19~${\upmu}$g/mL~\cite{60}. 

In other studies, an inverse effect of lipophilicity related to radical
scavenging activity was \mbox{reported~\cite{35,63}.} \textsc{l}-DOPA dipeptides
bearing glycine moiety \textbf{24} and \textbf{25} demonstrated higher
antiradical activity compared to \textsc{l}-DOPA peptide derivatives bearing
amino acid residues such as alanine, valine, leucine, phenylalanine,
methionine, and tryptophan~\cite{35}. The radical scavenging abilities
of isoquercitrin esters (C4--C10) decreased with  elongation of the
acyl chain length in both DPPH and ABTS assays~\cite{63}. 

The presence of unsaturation in the alkyl chain was reported to enhance
the radical scavenging activity. Hydroxytyrosyl oleate~\cite{58},
isoquercitrin oleate~\cite{63}, dopamine oleate~\cite{59}, and
\textit{N}-acyl-\textsc{l}-DOPA oleyl gemini surfactant~\cite{19} were found to
exhibit good radical scavenging abilities. This could be attributed to
the restriction in conformational freedom resulting from the
double-bond rigidity, which disfavors a folded conformation causing a
shielding effect of the phenolic moiety~\cite{49}. The nature of the
substituents attached to the phenolic moiety was also reported to
influence the scavenging ability. Compound \textbf{18} bearing a
trifluoromethyl moiety showed the highest DPPH radical scavenging
abilities (IC\tsub{50} ${=}$\ 17.13 ${\upmu}$M) and H\tsub{2}O\tsub{2}
free radical scavenging activity (IC\tsub{50} ${=}$\ 22.11 ${\upmu}$M) in
the series of reported \textsc{l}-DOPA urea derivatives~\cite{27}.

\subsection{Antibacterial activity}\label{ssec22}

The microbial resistance against antibiotics has encouraged
researchers to develop new compounds having enhanced antimicrobial
properties against a wide spectrum of pathogenic microbial strains.

\textsc{l}-Tyrosine and \textsc{l}-DOPA derivatives have been found to possess very good
antimicrobial effects against a broad range of bacteria due to the
presence of the phenolic group~\cite{64,65,66}. The physicochemical
properties, structure, and conformation of bioactive compounds have a
great influence on their bactericidal activity. Other important
factors, such as the hydrophilicity/lipophilicity balance of the
biomolecule and the cationic charge density, govern the antibacterial
activity of bioactive compounds~\cite{67}. Surfactants with different
alkyl chains have the ability to solubilize in lipid membranes and are
widely used as antibacterial agents due to their interactions with the
bacterial cell membrane. 

An increase in antibacterial activity depending on the chain length has
been reported, where the \mbox{optimal} effectiveness is generally observed at
a particular chain length called the cut-off point, usually between 8
and 14 carbons, where the biological activity increases as the alkyl 
chain increases, however, after reaching a threshold, the biological
activity starts to decrease~\cite{48,49}. The alkyl tyrosine (C8--C14)
and DOPA (C8--C14) ester ammonium hydrochlorides \textbf{2} were
reported to exhibit antimicrobial activity against a panel of gram
positive and gram negative bacteria. The authors reported that
compounds were more active against gram positive compared to gram
negative strains. The activity was found to increase by increasing the
chain length with a cut-off at C12 for gram positive bacteria and
C8/C10 for gram negative bacteria. The dodecyl alkyl esters displayed
highest antibacterial activity against \textit{S.~aureus}, with 
minimum inhibitory concentration (MIC)
value of 2.6~${\upmu}$M for the \textsc{l}-tyrosine and 249~${\upmu}$M for the
\textsc{l}-DOPA derivatives~\cite{2,60}. The lower antibacterial activity of the
DOPA derivatives was attributed to the stability of the intramolecular
hydrogen bonding between the two hydroxyl groups, and hence the
hydroxyl groups are less labile for further interaction with the
bacterial cell membrane. 

Cationic surfactants having a positively charged head group are known
to interact with the negatively charged bacterial membrane followed by
penetration into the nonpolar tail of the lipid bilayer of the
membrane causing cell lysis. Quaternary ammonium derivatives \textbf{3}
of both tyrosine (C10--C16) and DOPA (C10--C16) displayed higher
antibacterial activity than their corresponding alkyl ester ammonium
hydrochlorides due to the presence of one methyl and two ethyl groups,
which increase the hydrophobicity. The tetradecyl alkyl tyrosine showed
the highest antibacterial activity against \textit{S.~epidermidis} with an
MIC value of 1.7~${\upmu}$M while the \textsc{l}-DOPA analogue exhibited an MIC
value of 85~${\upmu}$M~\cite{12}. The authors also concluded that
antibacterial activity was mainly due to their monomers instead of
their micelles~\cite{2}.

Gemini surfactants exhibit higher antibacterial activity than
single-chain surfactants depending on various structural features such
as the alkyl chain length, spacer chain length, type of amino acid, and
the cationic net charge. It was observed that gemini surfactants with a
spacer chain of three carbon atoms and an alkyl chain length of
C10--C12 demonstrate optimum antibacterial activity~\cite{67}. The
\mbox{\textit{N}-acyl} tyrosine gemini surfactant \textbf{10} exhibited better
antibacterial activity against \textit{B.~cereus} compared to its
monomeric analogue, with an MIC value of 0.15~mM because of an increase
in hydrophobic interaction between the surfactant molecule and the
bacterial membrane. 

Monomeric surfactant \textbf{11} bearing unsaturation in the side
alkyl chain showed enhanced antibacterial activities compared to its
saturated  homologue \textbf{9} due to the double-bond
rigidity~\cite{18}. This was attributed to the right
lipophilic/hydrophilic balance and higher solubility. 

\textsc{l}-Tyrosine based thiol derivatives \textbf{16} exhibited potent
metallo-${\upbeta}$-lactamase IMP-1 competitive inhibition activity
($K_{\mathrm{ic}}$ ranging from 0.086 to 9.39~${\upmu}$M)~\cite{25}.
PEGylated dopamine ester \textbf{36} showed good antibacterial
activity against \textit{B.~subtilis}, \textit{S.~aureus},
\textit{P.~aeruginosa}, and \textit{P.~vulgaris} with zones of
inhibition ranging from 21 to 27~mm, which were comparable to the
positive control ampicillin~\cite{44}. Lipophilic tyrosyl ester
derivatives (C8--C12) \textbf{37} exhibited antibacterial activity
against \textit{S.~aureus}, \textit{S.~xylosus}, and \textit{B.~cereus}
with MIC in the range 3.1--25~${\upmu}$g/mL~\cite{48}, showing a
cutoff effect at C10.  

Schiff bases possess good antibacterial properties due to the presence
of the azomethine group, which increases hydrogen bonding interactions
with the proteins of the bacteria, subsequently inhibiting bacterial
growth. Compared to the positive control norfloxacin with MIC ${=}$\ 3.12
${\upmu}$g/mL, the Schiff base based on dopamine and 4-hydroxycoumarin
\textbf{33} exhibited higher antibacterial activity against 
\textit{E.~coli}, \textit{K.~pneumonia}, \textit{B.~subtilis}, and 
\textit{S.~aureus}, with MIC values ranging from 3.12 to
12.25~${\upmu}$g/mL, than its homologue \textbf{34} bearing isatin
moiety, which showed MIC values in the range 
6.25--50~${\upmu}$g/mL~\cite{46}.

\subsection{Antiproliferative activity}\label{ssec23}

Phenolic compounds possess interesting pharmacological properties,
including protective effects against neurodegenerative and cancer
diseases. Antiproliferative activity increases with the easy diffusion
of biomolecules into cell membranes, which depends on the balance
between hydrophobicity and lipophilicity~\cite{68,69,70}. 

A number of researchers reported potential applications of \textsc{l}-tyrosine
and \textsc{l}-DOPA derivatives for the treatment of certain types of \mbox{cancer.}
\mbox{Tyrosine} moieties may improve the therapeutic effect of existing
anticancer drugs such as chlorambucil. Tyrosine--chlorambucil methyl
ester \textbf{15a}, tyrosinol--chlorambucil \textbf{15b}, and
\textit{meta}-hydroxyphenyl--tyrosinamide--chlorambucil derivatives
\textbf{15c} displayed enhanced cytotoxic effects towards MCF-7 and
MDA-MB-231 cancer cell lines compared to chlorambucil. A spacer chain of
five carbon atoms between the tyrosine moiety and chlorambucil was
found to be beneficial compared to a spacer chain of ten carbon atoms.
This effect can be related to the cut-off effect discussed in the
previous section, where bioactive molecules demonstrate optimum activity
at a particular chain length. Tyrosine--chlorambucil derivatives with a
10-carbon spacer were reported to be inactive against the breast cancer
cell lines MDA-MB-231 probably due to the lower solubility arising from
the longer alkyl chain. The higher activity and selectivity towards the
cancer cell line MCF-7 over the cancer cell line MDA-MB-231 might be
attributed to the difference in cell morphologies~\cite{24}. The
presence of the alcohol functional group improves antiproliferative
activity over the ester functional group. Tyrosinol--chlorambucil analogues
showed higher activity than tyrosine--chlorambucil methyl ester analogues.
This can be attributed to the solubility promoted by the presence of
the hydroxymethyl function, which has a great influence on the
hydrophilicity/lipophilicity{\unskip\break} balance~\cite{23}.

Many studies have shown that acylation and esterification of \textsc{l}-tyrosine
and \textsc{l}-DOPA give rise to derivatives with antiproliferative properties
especially towards HeLa cells and MCF-7 cells with optimum activity.
Tyrosine based poly(ester--urethane) \textbf{4} and their
nanoparticles were employed as drug delivery (doxorubicin and
camptothecin) vehicles in cancer therapy and were found to be more
efficient on the cervical cancer cell line (HeLa) compared to free
drugs~\cite{13}. Tyrosine based hydroxamic acid \textbf{8}
exhibited greater histone deacetylase (HDAC8) inhibitory activity
(IC\tsub{50} ${=}$\ 0.15~${\upmu}$M) compared to the antitumor agent SAHA
(IC\tsub{50} ${=}$\ 1.48~${\upmu}$M) and displayed moderate
antiproliferative potency towards cancer cell lines such as MDA-MB-231,
A549, HCT-116, and HeLa cell nuclear extract~\cite{17}. 

Dimeric caffeic acid--\textsc{l}-DOPA hybrid \textbf{13} displayed
interesting and equipotent antiproliferative activities (IC\tsub{50}
${=}$\ 1.00~${\upmu}$M) for breast cancer cell lines \mbox{MDA-MB-231} and
MCF-7~\cite{22}. The antiproliferative activity displayed by 
lipophilic hydroxytyrosol ester \textbf{38} against human cervical HeLa
cells (IC\tsub{50} ${=}$\ 0.33~mM) was higher compared to the free
hydroxytyrosol (IC\tsub{50} ${=}$\ 0.46~mM), which was attributed to the
increase in permeability across cell membranes~\cite{50}. The
antiproliferative activity of hydroxytyrosol can also be enhanced by
attaching other bioactive compounds to the primary hydroxyl group
through the transesterification reaction. Ester \textbf{39} exerted
more potent antitumor activity towards the human colorectal
adenocarcinoma HT-29 cell line compared to the parent compounds
hydroxytyrosol and ${\upalpha}$-lipoic acid~\cite{52}.

\subsection{Anti-Parkinson activity}\label{ssec24}

Parkinson's disease is a progressive neurodegenerative disorder due to
the depletion of dopamine levels in the striatum area of the brain.
Therefore, the treatment of Parkinson's disease is based on the
restoration of dopamine, a neurotransmitter controlling movement in the
central nervous system~\cite{8}. 

Since dopamine cannot cross the blood--brain barrier (BBB) and penetrate
into the brain due to its large hydrophilicity, peripheral
administration of its precursor, \textsc{l}-DOPA, showed beneficial effects in
Parkinson's disease therapy~\cite{71}. The challenges associated with
the prodrug \textsc{l}-DOPA are its short half-life in plasma, poor solubility,
and therefore only 1\% of the administered \textsc{l}-DOPA can reach the
brain~\cite{72}. One of the strategies employed to enhance the
bioavailability of \textsc{l}-DOPA includes the development of prodrugs by
conjugation of \textsc{l}-DOPA with another moiety with the intention of
releasing \textsc{l}-DOPA after enzymatic cleavage of the prodrug~\cite{9}. 
Many researchers showed that functionalization of the hydroxyl,
carboxylic, and amino groups into \textsc{l}-DOPA ester and amide derivatives
improves the pharmacological response of  \textsc{l}-DOPA. Diacetylated
\textsc{l}-DOPA amide derivatives \textbf{5} generated sufficient and more
prolonged plasma levels of \textsc{l}-DOPA ($C_{\max} = 1746$ ng/mL;  $t_{1/2} =
97$ min) after its oral administration compared to the prodrug \textsc{l}-DOPA
($C_{\max}=4088~\mathrm{ng/mL}$; $t_{1/2} = 75$ min)~\cite{15}. 

Lee et~al.\ \cite{20} carried out in~vivo studies in the
6-hydroxydopamine rat model, which revealed that \textsc{l}-DOPA derivatives
\textbf{12} demonstrated therapeutic potential for Parkinson's disease
by increasing the level of dopamine in the brain by 2.2-fold~\cite{20}.
\textsc{l}-DOPA phosphoramidate \textbf{17} derived from serinate was found
to possess great potential for sustained release of \textsc{l}-DOPA at pH~7.4
with a half-life time of approximately 10~h~\cite{26}. 

In another study, \textsc{l}-DOPA tetrapeptide \textbf{22} maintained a
higher dopamine level and demonstrated significant bioavailability with
a plasma level of 110~${\upmu}$g/mL versus 75~${\upmu}$g/mL shown by
\textsc{l}-DOPA for 4~h post administration~\cite{33}. \textsc{l}-DOPA dipeptide
\textbf{23} tested in the 6-hydroxydopamine lesioned rat model,
demonstrated higher rotational response than \textsc{l}-DOPA with 149\% peak
activity of \textsc{l}-DOPA after 10 min of oral administration~\cite{34}. 

Diketopiperazine-containing propargyl moiety \textbf{20} displayed
enhanced BBB permeability with a permeability
coefficient  $P_{e} = 4.87 \times 10^{-6}$ cm/s compared to \textsc{l}-DOPA 
($P_{e} = 0.75 \times 10^{-6}$ cm/s)~\cite{31}. These findings
demonstrated that the design of an efficient \textsc{l}-DOPA prodrug is a
combination of various factors such as lipophilicity enhancement, size
and nature of the substituents, type of bond junction, either ester or
amide bond, as well as the hydrophilicity/lipophilicity balance.

\subsection{BSA binding abilities}\label{ssec25}

The potential use of a drug in clinical practice depends on its binding
ability to transport proteins. Serum albumins are the major proteins
found in the bloodstream (52--62\%)~\cite{73}. Human serum
albumin (HSA) and BSA are largely used in the development of drug
delivery systems. Being less expensive and structurally similar to HSA
by 76\%~\cite{74,75}, BSA is considered an appropriate model to
study the interaction between bioactive molecules and blood proteins.
BSA consists of 583 amino acid residues distributed into three domains
(I--III) with a predominantly ${\upalpha}$-helical content (55--68\%). 
The three domains---domain I with residues (1--195), II (196--383), and III
(384--583)---are assembled together by 17 disulfide
bridges, forming the pattern of a heart-shaped molecule. Each domain
is subdivided into two subdomains, A and B~\cite{76,77,78}. The
binding interaction of BSA with bioactive molecules is generally
investigated using various spectroscopic techniques, such as
steady-state fluorescence \mbox{quenching}, synchronous fluorescence,
UV--visible, FT-IR, and molecular docking studies~\cite{79,80}. The
main \mbox{fluorescence} emission properties of BSA arise from BSA chromophore
residues such as tryptophan (Trp), tyrosine (Tyr), and phenylalanine
(Phe) in the ratio Trp (100)/Tyr (9)/Phe (0.5)~\cite{79}. 

As the contribution of phenylalanine is negligible, many researchers
prefer to perform fluorescence emission studies by selectively exciting
tryptophan residues at 295 nm~\cite{81,82} or by exciting both
tryptophan and tyrosine residues at 280 nm~\cite{79,83,84}. Some
authors reported the contribution of Trp-212~\cite{85,86,87,88}
whereas others reported Trp-213~\cite{89,90}, but both agree on the
conclusion that the main binding site of BSA is located in the vicinity
of Trp-134 on the surface of subdomain IA and Trp-212 (Trp-213) within
the hydrophobic pocket of subdomain IIA. In view of clarifying the
major binding sites of biomolecules with BSA, warfarin and ibuprofen
have been extensively employed as binding site markers for subdomain
IIA (Trp-212/Trp-213) and subdomain IA (Trp-134),
respectively~\cite{91}.

The binding interactions of biomolecules with BSA are indicated by a
decrease in intrinsic fluorescence intensity of BSA combined with a red
shift~\cite{92,93,94} or a blue shift~\cite{83,95} due to changes in
the microenvironment of BSA chromophore residues.

The binding affinity of bioactive molecules with serum albumins provides
an indication of their distribution through the circulatory system;
therefore, bioactive molecules should be able to bind significantly to
the serum albumins. However, a stronger binding of a drug molecule with
albumin leads to a decrease in the concentration of the drug in plasma,
while a weakly bound drug has a shorter lifetime and poor distribution
in plasma~\cite{96}.

Binding constant values in the ranges  10\tsup{6}--10\tsup{8}
M\tsup{-1} and 10\tsup{3}--10\tsup{5} M\tsup{-1} witness strong and
moderate interactions, respectively, while a binding constant value
less than  10\tsup{2} M\tsup{-1} gives an indication of a weak BSA
binding interaction with biomolecules~\cite{82}. In general, a binding
constant  (${K}_{\mathrm{b}}$) ranging between 10\tsup{4} and
10\tsup{6} M\tsup{-1} is suitable for drug--carrier complexes within the
circulatory system~\cite{79,97}. The interaction of \textsc{l}-tyrosine and
\textsc{l}-DOPA derivatives with BSA has been reported, where \textsc{l}-tyrosine
derivatives interact more efficiently than \textsc{l}-DOPA derivatives. 

\textsc{l}-Tyrosine Schiff base \textbf{26} showed higher binding affinity
$({K}_{\mathrm{b}} = 1.11 \times 10^{4}~\mathrm{M}^{-1})$ with
BSA compared to \textsc{l}-DOPA Schiff base $({K}_{\mathrm{b}} = 0.96
\times 10^{4}~\mathrm{M}^{-1})$~\cite{38}.  The trend is in line with
the results reported by Ndayiragije et~al.\ \cite{39} for imine
derivatives \textbf{27} (${K}_{\mathrm{b}} = 3.04 \times
10^{6}~\mathrm{M}^{-1}$ versus  $1.55 \times 10^{5}~\mathrm{M}^{-1}$)
and \textbf{28}  (${K}_{\mathrm{b}} = 1.77 \times
10^{7}~\mathrm{M}^{-1}$ versus  $8.41 \times
10^{5}~\mathrm{M}^{-1}$)~\cite{39}. This can be attributed to the
participation of the two hydroxyl groups in intramolecular hydrogen
bonding, thereby lowering the availability of the hydroxyl group for
further interaction with BSA. 

\section{Physicochemical properties of \textsc{l}-tyrosine and \textsc{l}-DOPA
derivatives}\label{sec3}

\textsc{l}-DOPA and \textsc{l}-tyrosine derived surfactants are known to exhibit
interesting physicochemical properties owing to the presence of the
long hydrophobic chain, which is responsible for their applications in
the pharmaceutical as well as in the detergency field. In this section,
physicochemical properties in terms of critical micelle
concentration (CMC), surface tension, and spatial orientation of \textsc{l}-tyrosine
and \textsc{l}-DOPA amino acid based surfactants are\break discussed. 

\subsection{Critical micelle concentration}\label{ssec31}

Amino acid based surfactants have been known for their desirable
surface-active properties due to the formation of intra- and
intermolecular interactions that contribute to the self-assembly
process~\cite{98}. Due to their amphiphilic character, surfactants can
interact with biological membranes and improve drug
permeability~\cite{99}. 

When these amphiphilic compounds are adsorbed at the water interface
and reach a certain concentration, where all surfaces are saturated,
they self-assemble to form aggregates called micelles~\cite{100}. The
minimum concentration of the surfactants at which micellar formation
starts is called critical micelle concentration. The CMC values can
be determined using different techniques such as conductometric method,
tensiometry, and fluorescence spectrometry. Ionic surfactants generally
possess higher CMC values than nonionic surfactants, but for both types
of surfactants, their CMC values mainly depend on various factors such
as the length of the alkyl chain, solvent composition, temperature, and
the size of the polar head group. The micellization process of amphiphilic
molecules becomes more favorable with elongation of the lipophilic chain
or in the presence of a less polar head group, causing a decrease in
CMC values. The CMC \mbox{values} of \textsc{l}-tyrosine and \textsc{l}-DOPA based surfactants
are reported to decrease when the alkyl chain length increases.
\textsc{l}-Tyrosine derivatives \textbf{2} show CMC values ranging from 
1.940~mM to 0.013~mM (C8--C14)~\cite{2} while CMC values of DOPA
derivatives \textbf{3} range from 1.070~mM to 0.024~mM
(C10--C16)~\cite{12}.  A larger hydrophilic group weakens the
interfacial packing. Therefore, micellar formation becomes less
spontaneous, leading to higher CMC values~\cite{101}. \textsc{l}-DOPA
derivatives \textbf{3} (C10--C16) exhibit higher CMC values
(1.070~mM--0.024~mM) compared to their homologues, \textsc{l}-tyrosine
derivatives \textbf{3} (C10--C16, 1.038~mM--0.019~mM~)\cite{12}.

It has been reported in the literature that hydrophobicity constitutes
an important factor in causing a decrease in CMC values. Therefore, the
hydrophobic part of the molecule can predominate over the polar head
group~\cite{101,102}. Gemini surfactants, which are dimeric amphiphilic
compounds consisting of two hydrophobic and two hydrophilic groups per
molecule, micellize much easily compared to single-chain, monomeric
surfactants~\cite{67}. Gemini tyrosine derivative \textbf{10}
shows lower CMC values (0.050~mM) compared to monomeric tyrosine
derivative \textbf{9} (CMC ${=}$\ 0.117~mM)~\cite{18}.

\subsection{Surface tension}\label{ssec32}

Surface tension is a physicochemical property of liquids, which is
related to the intermolecular forces interacting over a liquid surface
area~\cite{103}. The surface tension linearly decreases with 
increase in concentration of surfactants, indicating that
surfactants are adsorbed at the air--solution interface. The
effectiveness of a surfactant molecule related to the surface tension
at the CMC ($\upgamma_{\mathrm{cmc}}$) corresponds to the maximum
reduction in interfacial tension. 

The presence of an additional hydroxyl group that contributes to an
increase in size of the polar head group for \textsc{l}-DOPA derivatives compared
to \textsc{l}-tyrosine derivatives increases the effectiveness of hydroxytyrosol
decanoate ($\upgamma_{\mathrm{cmc}} = 28.0$ mN/m) compared to tyrosol
decanoate ($\upgamma_{\mathrm{cmc}} = 41.5$ mN/m)~\cite{51}.

The Gibbs surface excess ($\Gamma_{\max}$) and the minimum area
occupied by a surfactant molecule ($A_{\min}$) are two important
interfacial parameters determining the adsorption behavior and packing
density. The Gibbs surface excess can be calculated from the Gibbs
adsorption equation (Equation~(\ref{eq1})):
{\begin{equation}\label{eq1}
\Gamma _{\max} = \dfrac{-1}{2.303 n'RT}
\left(\dfrac{\delta \gamma }{\delta \log C}\right)
\end{equation}}\unskip
where $R$ is the gas constant (8.314~J/mol$\cdot$K), $T$ is the absolute
temperature (298~K), $C$ is the surfactant concentration,
$\bgamma$ is the surface tension, and $n$ denotes
the effective number of species in the solution~\cite{104,105}. The Gibbs
surface excess ($\Gamma_{\max}$) increases by increasing the
surfactant concentration and the alkyl chain length due to stronger
hydrophobic/hydrophobic interactions pushing a maximum number of
surfactant molecules to the surface~\cite{106,107}. The minimum area
occupied by the surfactant molecule ($A_{\min}$) can be calculated
from the Gibbs equation (Equation~(\ref{eq2})): 
{\begin{equation}\label{eq2}
A_{\min} = \dfrac{10^{18}}{N \Gamma_{\max}}
\end{equation}}\unskip
where $A_{\min}$ is the minimum area per surfactant molecule at the
saturated interface and $N$ is the Avogadro number ($N = 6.022 \times
10^{23}$).

Higher values for $A_{\min}$ are an indication of poor packing at the
interface, and this parameter varies in the opposite manner with
$\Gamma_{\max}$. Hydroxytyrosol octanoate and hydroxytyrosol decanoate
showed higher values 
(C8: $A_{\min} = 48.4$~\AA{}\tsup{2}, 
C10: $A_{\min} = 39.4$~\AA{}\tsup{2}) compared to their corresponding tyrosol derivatives with the same chain length 
(C8: $A_{\min} = 35.3$~\AA{}\tsup{2}, 
C10: $A_{\min} = 32.0$~\AA{}\tsup{2}). The minimum surface
area decreases with elongation of the alkyl chain, resulting in
lower values being displayed by \textsc{l}-DOPA/\textsc{l}-tyrosine derivatives with a
C10 alkyl chain length 
(C10: $A_{\min} = 39.4$~\AA{}\tsup{2}/C10: $A_{\min} =
32.0$~\AA{}\tsup{2}) compared to \textsc{l}-DOPA/\textsc{l}-tyrosine derivatives with a
C8 alkyl chain length 
(C8: $A_{\min} = 48.4$~\AA{}\tsup{2}/C8: $A_{\min} =
35.3$~\AA{}\tsup{2})~\cite{51}.
The \textit{N}-dodecanoyl-\textsc{l}-DOPA methyl ester also showed lower values
($A_{\min} = 6.6$~\AA{}\tsup{2}) compared to the
\textit{N}-decanoyl-\textsc{l}-DOPA methyl ester 
($A_{\min} = 6.7$~\AA{}\tsup{2})~\cite{19}. 

\subsection{Spatial orientation}\label{ssec33}

The spatial orientation of surfactants in a specific medium may play an
integral part in affecting the biological activity of systems due to
the way they penetrate into the cell membrane. 

Joondan et~al.\ \cite{12} investigated the change in conformation of a
quaternary ammonium derivative of \textsc{l}-tyrosine \textbf{3}. 
Nuclear magnetic resonance (NMR) studies
showed a distinct shielding of the protons of both the ethyl and methyl
groups attached to the quaternary ammonium moiety due to ring current
effect, which suggests the proximity of the aromatic protons with the
quaternary ammonium moiety. The authors concluded that the \textsc{l}-tyrosine
and \textsc{l}-DOPA quaternary ammoniums adopt a similar conformation in the
aqueous layer, whereby the head group includes the quaternary ammonium
moiety and the phenolic group. The higher CMC of the \textsc{l}-tyrosine and
\textsc{l}-DOPA quaternary ammoniums was attributed to the bulkiness of the head
group, which caused less efficient packing of the molecules at the
interface~\cite{12}. These results were also confirmed by using 2D NMR
to determine the spatial orientation of surfactants.{\vspace*{-2pt}}

\section{Conclusion}

The presence of three different functional groups such as carboxylic,
amino, and hydroxyl groups on \textsc{l}-tyrosine and \textsc{l}-DOPA backbones offers a
possibility of designing and developing multiple structures with
potential industrial applications. Physicochemical and biological
properties of \textsc{l}-DOPA and \textsc{l}-tyrosine derivatives are affected by the
length, the unsaturation of the alkyl chain, and the presence
of other functional groups attached to the \textsc{l}-tyrosine or \textsc{l}-DOPA
scaffold. The major challenges in the synthesis of \textsc{l}-tyrosine and
\textsc{l}-DOPA derivatives lie in the use of various protecting groups as well
as low yield of products. Our group is contributing to the synthesis of
new \textsc{l}-tyrosine and \textsc{l}-DOPA derivatives with promising physicochemical
and biological properties.{\vspace*{-2pt}} 

\section*{Declaration of interests}

The authors do not work for, advise, own shares in, or receive funds
from any organization that could benefit from this article, and have
declared no affiliations other than their research organizations.
{\vspace*{-2pt}}

\section*{Acknowledgments}

EN is grateful to the Higher Education Commission (HEC) of Mauritius
for the grant of scholarship through Mauritius Africa Scholarship
Scheme 2021 and the University of Mauritius for providing research
facilities. 

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