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\def\citeauthor{~Gomedhika~P~M,
              ~Subhashini~NJP}
\def\citetitle{\textit{In vitro} anti-proliferative activity of newly synthesized compounds of substituted-(3-phenyl-1,2,4-oxadiazol-5yl)-methyl-9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzocyclohepten-8-carboxylates}
\def\copyrightstmt{This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial- ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.}
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\begin{document}


\def\RunningAuthor{Subhashini NJP and Gomedhika P M}
\firstPage{91}
\articleType{Original Article}
\receivedDate{23 Feb 2022}
\acceptedDate{12 Mar 2022}
\revisedDate{10 Mar 2022}
\journalVolume{2}
\journalIssue{2}
\journalDoi{fjphs.v2i2.237}
\copyrightYear{2022}
\eISSN{2583-116X}
\journalDoi{fjphs.v2i2.237}
\def\authorCount{2}
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\def\journalTitle{Future Journal of Pharmaceuticals and Health Sciences}

\title{\textit{In vitro} anti-proliferative activity of newly synthesized compounds of substituted-(3-phenyl-1,2,4-oxadiazol-5yl)-methyl-9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzocyclohepten-8-carboxylates}
\author{Gomedhika~P~M, 
            Subhashini~NJP\textsuperscript{*}~\\[5pt]{Department of Chemistry, Osmania University, Hyderabad-500 007, Telangana, India}}

\begin{abstract}
A series of the newly synthesized substituted-(3-phenyl-1,2,4-oxadiazol-5yl)-methyl-9-chloro-2,3-dimethyl-6,7-dihydro-5\textit{H}-benzocyclohepten-8-carboxylates 13a-h have been assessed for their anti-proliferative activity \textit{in vitro} and shown negative effect with GI\ensuremath{_{50}} values 0.320-4.750 \textit{\ensuremath{\mu}}M towards cancer cell growth. The compounds 13d, 13e, 13f, 13g showed significant activity towards three cancer cell lines of human. Among them 13 gm showed strong anti-cancer activity towards PANC-1 at 0.312  \textit{m}M respectively. Notably, compound 13e showed significant activity at 0.320  \textit{m}M against MDA MB-231 respectively.  
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}American Type Culture Collection,\newline MDA MB 231,\newline PANC-1
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright{\Large$^\ast$}Corresponding Author\par Name:\ Subhashini~NJP~\\ Phone:\ ~\\  Email:\ njsubhashini@yahoo.co.in
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\section{Introduction}
With the discovery of Colchicine \unskip~\cite{1372763:24580624,1372763:24580774}  (I), the anticancer effect of benzosuberone has been raised since 1984. In drug discovery program Benzosuberone, which contain the core structure take a different role, particularly in natural products. The associated components of benzosuberone have been marvellous agents for therapeutic purpose as cytotoxic \unskip~\cite{1372763:24580938,1372763:24581035,1372763:24580993}, anticancer \unskip~\cite{1372763:24581116,1372763:24581117}, CB1 (high) receptors \unskip~\cite{1372763:24581115}, anti-malarial \unskip~\cite{1372763:24581113}  and strong activity of antagonistic \unskip~\cite{1372763:24581115}. Here, few new analogues of benzosuberone \unskip~\cite{1372763:24581312,1372763:24581112}, (II-IV) represent in Figure~\ref{f-d248f9fe2943}  are proved to be effective as tubulin (polymerization inhibitors). 
    
\section{MATERIALS AND METHODS}
Required human cancer cell lines (MDA MB 231, He La, and IMR 32, MIAPACA, and SIHA, PANC-1) procured from American Type Culture Collection (ATCC), US.

\textbf{Methodology }

The newly synthesized compounds 13a-h \unskip~\cite{1372763:24581111} were analysed according to usual reported method for their anti-proliferative activity for three various cancer cell lines of human as SIHA, MDA MB 231, PANC-1 \textit{in vitro}. A protocol of drug exposure for 48h continuously and SRB cell proliferation assay was used for estimation viability or growth of cell. In a humidified atmosphere containing 10\% FBS and 5\% CO\ensuremath{_{2}} at 37 \ensuremath{^\circ}C for growth of cell lines (Dulbecco's modified Eagle's medium). Cells were trypsinized and aliquots at plating densities based on the individual cell lines doubling time, from T25 flasks/60 mm dishes sub-confluent and 96-well plates in 100 \ensuremath{\mu }L were seeded.


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\centering \makeatletter\IfFileExists{images/a7414392-ac3b-43ee-8c84-d76de2836e9c-upicture1.png}{\includegraphics{images/a7414392-ac3b-43ee-8c84-d76de2836e9c-upicture1.png}}{}
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\caption{\boldmath {Benzocycloheptenone Core Structure with Biological Importance}}
\label{f-d248f9fe2943}
\end{figure}
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\caption{\boldmath {Schemes of the Tested Compounds (13a-h)}}
\label{f-b4a7651cf1c0}
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\caption{\boldmath {(GI\ensuremath{_{50}}/\ensuremath{\mu}M)\ensuremath{^{a}} Values of the Tested Compounds (13a-h) }}
\label{f-9e39e8efa9c8}
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\egroup

\begin{table*}[!htbp]
\caption{\boldmath {(GI\ensuremath{_{50}}/\ensuremath{\mu}M) Values of the Tested Compounds (13a-h) } }
\label{tw-fc2326cdeea0}
\def\arraystretch{1.1}
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\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0939\linewidth-2\tabcolsep}p{\dimexpr.29439999999999998\linewidth-2\tabcolsep}p{\dimexpr.2017\linewidth-2\tabcolsep}p{\dimexpr.2216\linewidth-2\tabcolsep}p{\dimexpr.1884\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack S. No & \cAlignHack Compound & \cAlignHack SIHA  & \cAlignHack MDAMB-231 & \cAlignHack PANC-1\\
\tblmidrule 
\cAlignHack 1 &
  \cAlignHack 13a  &
  \cAlignHack 4.750 \ensuremath{\pm}0.07 &
  \cAlignHack 2.800 \ensuremath{\pm}0.02 &
  \cAlignHack 2.155 \ensuremath{\pm}0.02\\
\cAlignHack 2 &
  \cAlignHack 13b  &
  \cAlignHack 3.530 \ensuremath{\pm}0.01 &
  \cAlignHack 2.500 \ensuremath{\pm}0.03 &
  \cAlignHack 1.290 \ensuremath{\pm}0.04\\
\cAlignHack 3 &
  \cAlignHack 13c &
  \cAlignHack 2.650 \ensuremath{\pm}0.02 &
  \cAlignHack 4.280 \ensuremath{\pm}0.07 &
  \cAlignHack 2.421 \ensuremath{\pm}0.03\\
\cAlignHack 4 &
  \cAlignHack 13d  &
  \cAlignHack 1.140 \ensuremath{\pm}0.05 &
  \cAlignHack 1.475 \ensuremath{\pm}0.05 &
  \cAlignHack 0.612 \ensuremath{\pm}0.05\\
\cAlignHack 5 &
  \cAlignHack 13e  &
  \cAlignHack 1.411 \ensuremath{\pm}0.06 &
  \cAlignHack 0.320 \ensuremath{\pm}0.01 &
  \cAlignHack 0.670 \ensuremath{\pm}0.07\\
\cAlignHack 6 &
  \cAlignHack 13f  &
  \cAlignHack 0.972 \ensuremath{\pm}0.02 &
  \cAlignHack 0.860 \ensuremath{\pm}0.06 &
  \cAlignHack 0.633 \ensuremath{\pm}0.01\\
\cAlignHack 7 &
  \cAlignHack 13g  &
  \cAlignHack 1.109 \ensuremath{\pm}0.02 &
  \cAlignHack 0.370 \ensuremath{\pm}0.02 &
  \cAlignHack 0.312 \ensuremath{\pm}0.04\\
\cAlignHack 8 &
  \cAlignHack 13h  &
  \cAlignHack 0.650 \ensuremath{\pm}0.04 &
  \cAlignHack 0.660 \ensuremath{\pm}0.05 &
  \cAlignHack 0.950 \ensuremath{\pm}0.08\\
\cAlignHack 9 &
  \cAlignHack Cambretostatin(CA4)\ensuremath{^{b}} &
  \cAlignHack 0.05 \ensuremath{\pm}0.001 &
  \cAlignHack 0.019 \ensuremath{\pm}0.001 &
  \cAlignHack {\textless}0.01\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

    
\section{RESULTS AND DISCUSSION}
\textbf{Compounds Effects on the Viability of Human Cancer Cells} \textbf{\space }

The anti cancer activity \textit{in vitro} of the compounds 13a-h was observed against three various cancer cell lines of human SIHA (uterus), MDA-MB-231 (breast), PANC-1(pancreatic) summarised in the Table~\ref{tw-fc2326cdeea0} (Figure~\ref{f-b4a7651cf1c0}, Figure~\ref{f-9e39e8efa9c8}). Compounds were chosen for an advanced assay against four cancer cell lines of human at five different concentrations (0.01, 0.1, 1, 10, 100 \ensuremath{\mu}M). GI\ensuremath{_{50}} was calculated. As compared with standard Combretostatin these values in arrangement to concentration of the compound causing 50\% net cell growth decrease. For each one of these parameters results were calculated.

According to Table~\ref{tw-fc2326cdeea0}, 13a-h the synthesised series of compounds have shown negative towards the growth of cancer cell with GI\ensuremath{_{50}} values (0.312-4.750 \textit{\ensuremath{\mu}}M). Benzocycloheptenone of various substituents activity was examined. Based on demonstration many of the compounds show moderate cytotoxicities to the cell lines and can be compared with the activity to the +ve control of Combretostatin. 
    
\section{CONCLUSION}
In conclusion, with subject to Table above, the newly synthesized a series of compounds 13a-h with GI\ensuremath{_{50}} values (0.320-4.750 \textit{\ensuremath{\mu}}M) have shown effect on cancer cell growth inhibition. On dimethyl-benzocycloheptenone the effect of various substituents was analysed. The compounds 13d, 13e, 13f, 13g showed good activity towards three cancer cell lines of human. Among them 28k showed strong anti-cancer activity towards PANC-1 at 0.312 \textit{m}M respectively. Notably, compound 13e showed significant activity at 0.320  \textit{m}M against MDA MB-231 respectively.
    
\section{ACKNOWLEDGEMENT}
Authors are grateful to the Head, Department of Chemistry, Osmania University, Hyderabad, India.

\textbf{Conflict of Interest}

The authors attest that they have no conflict of interest in this study.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.

\textbf{F}\textbf{uture}\textbf{\space }\textbf{Perspectives} \textbf{\space }

Benzosuberone based compounds form an important class of benzofused heterocycles with a wide spectrum of biological activities such as anti-cancer. Many compounds are in development phase as potential new drugs acting against different targets. A literature survey revealed that modification on benzosuberone pharmacophore may results in increase in its biological potencies.
    

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