The Synthesis, Anticancer Activity, Structure-Activity Relationships and Molecular Modelling Studies of Novel Isoindole-1,3(2H)-dione Compounds Containing Different Functional Groups

Author(s):

Ayse Tan*, Serap Kizilkaya, Unzile Kelestemur, Atilla Akdemir and Yunus Kara   Pages 1368 - 1378 ( 11 )

Abstract:

<P>Background: Isoindole-1,3(2H)-dione derivatives are known to have cytotoxic effects on many cancer cells. The anticancer activity of these compounds varies depending on the substituents attached to them. Therefore, the effect of substituents is very important when determining the anticancer activities of molecules. We have recently reported an example of the substituent effect. </P><P> According to that work, the anticancer activity against HeLa, C6, and A549 cancer cell lines of isoindole- 1,3(2H)-dione compounds containing tert-butyldiphenylsilyl ether, azido, and hydroxyl groups was examined by our group. It was found that an isoindole-1,3(2H)-dione compound containing both tert-butyldiphenylsilyl ether group and azido groups showed higher anticancer activity than 5-fluorouracil and another isoindole-1,3(2H)- dione compound containing both azido and hydroxyl groups. </P><P> After we discovered that tert-butyldiphenylsilyl ether group in the skeletal structure of isoindole-1,3(2H)-dione exhibits anticancer activity against HeLa, C6, and A549 cancer cell lines, we wanted to examine the anticancer activities of different silyl ether groups, i.e., OTMS, -OTBDPS, and -OTBDMS groups, and also -OH and -Br groups, by comparing them with each other according to the structure–activity relationship. </P><P> Methods: All of the synthesized compounds were characterized by 1H and 13C NMR spectra, IR spectroscopy, and mass spectra measurements. The IC50 values of these compounds were calculated for all cancer cell lines and compared with each other and cisplatin, which is a platinum-containing chemotherapeutic drug. Molecular modelling studies were carried out using the MOE software package. </P><P> Results: It was found that compounds 13 and 16, containing both silyl ether (-OTBDMS) and -Br groups, showed higher anticancer activity than cisplatin against both Caco-2 and MCF-7 cell lines. Compounds 20 and 23 showed anticancer activity in MCF-7 cells and compounds 8, 9, 20, and 23 in Caco-2 cells. While compounds 20 and 23 have only a silyl ether (-OTMS) group, compounds 8 and 9 have only a -OH group. Molecular modelling studies indicated that compounds 8 and 13, as well as their analogs, may bind to the active site of hRS6KB1 (pdb: 4l3j), compound 11 may bind to the active site of human mTOR (pdb: 4jt5) and additionally, compounds 10-17 are expected to be both mutagenic and reactive according to the mutagenicity and reactivity calculations. </P><P> Conclusion: According to these results, the anticancer activities of isoindole-1,3(2H)-dione compounds (8 - 23) vary depending on the groups they contain and these groups affect each other&#039;s activities. Silyl ethers (-OTBDMS and -OTMS) and -OH and -Br groups in the skeletal structure of isoindole-1,3(2H)-dione can be regarded as anticancer agents. In this sense, compounds 13 and 16, containing both silyl ether (-OTBDMS) and - Br groups, may be regarded as alternative chemotherapeutic drugs. This work may lead to the synthesis of new isoindole-1,3(2H)-dione compounds containing different silyl ether groups and studies evaluating their anticancer activities or other biological properties.</P>

Keywords:

Isoindole-1,3(2H)-dione, trimethylsilyl ether, tert-butyldiphenylsilyl ether, tert-butyldiphenylsilyl ether, MCF-7, Caco-2, molecular modeling.

Affiliation:

Vocational School of Technical Sciences, Mus Alparslan University, Mus 49250, Department of Chemistry, Faculty of Arts and Sciences, Mus Alparslan University, Mus 49250, School of Health, Mus Alparslan University, Mus 49250, Computer-Aided Drug Discovery Laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul 34093, Department of Chemistry, Faculty of Sciences, Ataturk University, Erzurum 25240

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