Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines PMID: 24387982

ADC Targets in Oncology

2026-04-10

Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell lines

Bioorg Med Chem. 2014 Jan 15;22(2):738-55. doi: 10.1016/j.bmc.2013.12.015.

Dmitry V Demchuk ¹ , Alexander V Samet ² , Natalia B Chernysheva ³ , Vladimir I Ushkarov ⁴ , Galina A Stashina ⁵ , Leonid D Konyushkin ⁶ , Mikhail M Raihstat ⁷ , Sergei I Firgang ⁸ , Alex A Philchenkov ⁹ , Michael P Zavelevich ¹⁰ , Ludmila M Kuiava ¹¹ , Vasyl F Chekhun ¹² , Dmitry Yu Blokhin ¹³ , Alex S Kiselyov ¹⁴ , Marina N Semenova ¹⁵ , Victor V Semenov ¹⁶

Affiliations

1. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
2. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
3. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
4. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
5. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
6. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
7. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; Chemical Block Ltd, 3 Kyriacou Matsi, 3723 Limassol, Cyprus. Electronic address: [email protected].
8. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation. Electronic address: [email protected].
9. R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: [email protected].
10. R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: [email protected].
11. R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: [email protected].
12. R.E. Kavetsky Institute of Experimental Oncology, Pathology and Radiobiology, National Academy of Sciences of Ukraine, 45 Vasyl'kivska Street, 03022 Kyiv, Ukraine. Electronic address: [email protected].
13. Department of Biological and Medicinal Chemistry, Moscow Institute of Physics and Technology, Institutsky Per. 9, Dolgoprudny, Moscow Region, 141700, Russia. Electronic address: [email protected].
14. ChemDiv, 6605 Nancy Ridge Drive, San Diego, CA 92121, USA. Electronic address: [email protected].
15. Chemical Block Ltd, 3 Kyriacou Matsi, 3723 Limassol, Cyprus; N.K. Kol'tsov Institute of Developmental Biology RAS, 26 Vavilov Street, 119334 Moscow, Russian Federation. Electronic address: [email protected].
16. N.D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; Chemical Block Ltd, 3 Kyriacou Matsi, 3723 Limassol, Cyprus. Electronic address: [email protected].

Abstract

A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model. Structure-activity relationship studies identified compounds substituted with 3,4,5-trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human Cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C-C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N-C geometry). Compound 10ad' induced G2/M cell cycle arrest and Apoptosis in human T-leukemia Jurkat cells via Caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode.

Keywords

1,2,3-Triazole; AODAGYGNZDUVNE-UHFFFAOYSA-N; ASLUYQCBIKMJEU-UHFFFAOYSA-N; Apoptosis; B-cell lymphoma 2; BKSKBNPDOWPAIO-UHFFFAOYSA-N; BLZMTDZGGLTDRK-UHFFFAOYSA-N; Bcl-2; CA2; CA4; CA4 disodium phosphate; CA4P; Caspases; DGTARDXIKVVWRO-UHFFFAOYSA-N; DOZOVRQLBANESF-UHFFFAOYSA-N; FODBYKDYGDVMRL-UHFFFAOYSA-N; FXJWTEDHYUZWTB-UHFFFAOYSA-N; GMMZILPCMBXPAN-UHFFFAOYSA-N; GZOVKXTXKMUHLY-UHFFFAOYSA-N; HDKAKWQYWMYIBD-UHFFFAOYSA-N; HHGRWXNBXGCVQC-UHFFFAOYSA-N; IMOWNIZUMDTJSQ-UHFFFAOYSA-N; JHZMSGCUGQSNOA-UHFFFAOYSA-N; JNDJXILHVKVNJP-UHFFFAOYSA-N; KAADNOIRUAPIJA-UHFFFAOYSA-N; KSXSFROOOPRMBN-UHFFFAOYSA-N; LDAGHTYWGJDFRH-UHFFFAOYSA-N; MNDDRAXBOYBUGK-UHFFFAOYSA-N; Microtubule destabilizing agents; MoAb; OXFHSVYQNFVGTK-UHFFFAOYSA-N; PARP-1; PI; PLIMGILENGQOOC-UHFFFAOYSA-N; Plant polyalkoxybenzenes; QZZHJHZNLFRILP-UHFFFAOYSA-N; SAR; Sea urchin embryo; VFOXVLIPSYMQEK-UHFFFAOYSA-N; VYIKEPOZDAQBBG-UHFFFAOYSA-N; X-linked inhibitor of apoptosis; XAYFGZPYFSZKTA-UHFFFAOYSA-N; XIAP; YZUDFBGHMYEADF-UHFFFAOYSA-N; combretastatin A-2; combretastatin A-4; monoclonal antibody; poly(ADP-ribose) polymerase-1; propidium iodide; structure–activity relationship.