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Investigating isoquinoline derivatives for inhibition of inhibitor of apoptosis proteins for ovarian cancer treatment

Authors Chen C, Wu J, Zhu P, Xu C, Yao L

Received 21 March 2017

Accepted for publication 30 June 2017

Published 11 September 2017 Volume 2017:11 Pages 2697—2707

DOI https://doi.org/10.2147/DDDT.S137608

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Rammohan Devulapally

Peer reviewer comments 3

Editor who approved publication: Dr Qiongyu Guo

Chen Chen,1,* Jie Wu,2,* Pengfei Zhu,3 Congjian Xu,1 Liangqing Yao1

1Obstetrics and Gynecology Hospital and Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 2Department of Chemistry, Fudan University, Shanghai, 3Department of Obstetrics and Gynecology, Shangyu City Hospital, Shangyu, Zhejiang Province, People’s Republic of China

*These authors contributed equally to this work

Objective: To discover novel isoquinoline derivatives for inhibition of inhibitor of apoptosis proteins (IAP) for the treatment of ovarian cancer.
Methods: We first synthesized 533 isoquinoline derivatives, and screened them using CCK-8 to measure their antiproliferative activity. These compounds were further tested by Hoechst staining and flow cytometric analysis to assess proapoptotic activity. The in vivo antitumor efficacy and safety of the screened compounds were evaluated on the xenograft mouse model. Ki-67 staining and TUNEL assay were used to evaluate proliferation and apoptosis in the resected tumors, respectively. Western blot and polymerase chain reaction (PCR) were conducted to evaluate the levels of proliferating cell nuclear antigen (PCNA), caspase-3, PARP, and IAP in resected tumors.
Results: Compound B01002 and C26001 displayed antiproliferative and proapoptotic activity on SKOV3 ovarian cancer with an IC50 of 7.65 and 11.68 µg/mL, respectively. Both compounds inhibited tumor growth in a xenografted mouse model with good safety profiles, and tumor growth inhibition (TGI) of B01002 and C26001 was 99.53% and 84.23%, respectively. Resected tumors showed that both compounds inhibited tumor cell proliferation and induced apoptosis in vivo. Caspase-3 and PARP were activated, whereas IAP proteins were downregulated at the protein level.
Conclusion: Compound B01002 and C26001 could inhibit ovarian tumor growth and promote tumor apoptosis, partly by downregulating the IAPs, and, thus, might be promising candidates for treatment of ovarian cancer.

Keywords: isoquinoline derivatives, target-oriented syntheses, IAP inhibitor, chemotherapy, ovarian cancer

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