Abstract 4847: Discovery, semisynthesis, and structure-activity relationship studies of hirsutinolide derivatives as new STAT3 inhibitors and anti-glioma agents

Abstract

Abstract Clinically, natural product has played a pivotal role in anticancer drug discovery and development. Cancer chemotherapy and/or radiotherapy due to glioma treatment are not ideal, frequently cause unwanted adverse effects, and justify further research and development of alternative, novel, safe, and effective agents. In our continued efforts to identify new signal transducer and activator of transcription 3 (STAT3) and antiglioma agents with enhanced efficacy and specificity, we have initiated a collaborative and multidisciplinary natural product drug discovery project and the goal was to isolate, semisynthesize, and evaluate the potential of Vernonia cinerea-derived phytochemicals as STAT3 inhibitors with therapeutic remedy of human glioma and may be even more effective than the existing ones. To date, our preliminary studies have been conducted and resulted in the discovery of a class of sesquiterpene lactone hirsutinolide series with an á,â-unsaturated-ã-lactone ring as new STAT3 inhibitors. Specifically, on the basis of encouraging biological data and to expand the existing structure activity relationship (SAR) of isolated natural hirsutinolide analogues, chemical modifications were performed using conventional Steglich esterification protocol to produce a series of semisynthetic hirsutinolide derivatives in moderate to high yields. Thus far, biological evaluation revealed that several semisynthetic analogues showed low micromolar inhibitory activities against constitutively-active STAT3 and malignant glioma phenotype. SAR showed that a bulky and lipophilic ester functionality at position 13 is essential for STAT3 inhibition as well as whole cell based anticancer activity. A lipophilic side chain at position 8 also plays an important role in anticancer activity and may contribute a detrimental effect on specificity. In addition, the methoxy group at position 1 enhances the cell-type specificity and selectivity. Finally, selected promising lead candidates also demonstrated in vivo efficacy following oral gavage delivery, inhibiting human glioma tumor growth in subcutaneous mouse xenografts. Together, natural and chemically modified hirsutinolide-type sesquiterpene lactones represent a promising natural product class of new anticancer agents for the treatment of malignant human glioma. Citation Format: Mingming Zhang, Ui Joung Youn, Gabriella Miklossy, Supakit Wongwiwatthananukit, James Turkson, Leng Chee Chang, Dianqing Sun. Discovery, semisynthesis, and structure-activity relationship studies of hirsutinolide derivatives as new STAT3 inhibitors and anti-glioma agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4847.