Synthesis and anti-OXPHOS, antitumor activities of DLC modified spinosyn derivatives

Bioorg Med Chem Lett. 2020 May 1;30(9):127047. doi: 10.1016/j.bmcl.2020.127047.

Da-You Ma ¹, Qin Lai ², Kun-Jian Peng ³, Long-Long Wang ², Zeng-Xia Li ⁴, Li-Jun Liu ³, Zhi-Yong Luo ³, Su-You Liu ⁵

Affiliations

1 School of Pharmaceutical Sciences, Central South University, Changsha 410013, China. Electronic address: madayou@hotmail.com.
2 School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
3 School of Life Sciences, Central South University, Changsha 410013, China.
4 Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
5 School of Pharmaceutical Sciences, Central South University, Changsha 410013, China. Electronic address: liusuyou@hotmail.com.

PMID: 32139325 DOI: 10.1016/j.bmcl.2020.127047

Abstract

A series of DLC (delocalized lipophilic cation) modified spinosyn derivatives were synthesized and evaluated for antitumor efficacies both in vitro and in vivo. Cancer cell based antiproliferative assays indicated that the more lipophilic derivatives had stronger inhibitory effects on the tested Cancer cell lines. Compound 7b and 8b exhibited strong anti-OXPHOS and Apoptosis inducing ability. Notable antitumor efficacies of 7b (5 mg/kg) and 8b (2.5 mg/kg) were observed in the in vivo tumor xenograft experiments, however, lethal toxicities were observed on higher dosages. Our findings indicated that DLC modification is a viable strategy to enhance the anti-OXPHOS and antitumor efficacies of spinosyn derivatives.

Keywords

Antitumor activity; Delocalized lipophilic cation; Mitochondria; OXPHOS; Spinosyn.

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