Compound Discovery and Structure-Activity Relationship Study of Neoantimycins Against Drug-Resistant Cancer Cells.

Xiao Lin,Liyun Liu,Ling Chai,Fan Sun,Yongjun Zhou,Shihai Xu,Hongrui Zhu,Hou-Wen Lin,Shuping Wang,Buming Liu,Yeping Chen

doi:10.3389/fchem.2019.00481

Abstract

Four neoantimycins H-K (1–4) with C1-keto, including the new ones (1–2), were isolated from the culture of Streptomyces conglobatus RJ8. After enzymatically converting into their respective reduced type derivatives (5–8) in vitro, the absolute structures of 1–8 were established/reconfirmed by analyzing hydrolyzed components. The obtained NATs (4, 7, and 8) exhibited excellent cytotoxicity against drug-resistant colon and gastric cancer cells but low toxicity in the noncancerous cell. Further SAR investigation suggested that C1-hydroxyl, C9-isobutyl, and N-formyl contribute to the antiproliferation remarkably.

Highlights

Neoantimycins (NATs), a ring-expanded subfamily of antimycin, were thrust into the limelight in recent years (Lim et al, 2016; Liu et al, 2016; Awakawa et al, 2018; Skyrud et al, 2018)
Subfraction B1J5 was purified by semi-preparative HPLC (Waters Xbridge C18, 10 × 250 mm, 3 mL/min) under isocratic conditions using 70% aqueous acetonitrile with 0.1% formic acid as buffer to yield neoantimycin J (1) (8.9 mg, tR = 29.0 min) and K (2) (7.4 mg, tR = 23.0 min)
Subfraction B1J7P3 was further purified by semi-preparative HPLC (Waters Xbridge C18, 10 × 250 mm, 3 mL/min) under isocratic conditions using 70% aqueous acetonitrile with 0.1% formic acid as the buffer to yield neoantimycin I (4) (62 mg, tR = 19.0 min)

Summary

INTRODUCTION

Neoantimycins (NATs), a ring-expanded subfamily of antimycin, were thrust into the limelight in recent years (Lim et al, 2016; Liu et al, 2016; Awakawa et al, 2018; Skyrud et al, 2018). Unlike antimycins, inducing cancer cell apoptosis by inhibiting Bcl2/Bcl-xL-related anti-apoptotic proteins or mitochondrial electron transport, NATs were characterized as down-regulators of GRP-78 (Umeda et al, 2005; Izumikawa et al, 2007; Ueda et al, 2008; Kozone et al, 2009). The inhibition of Ras PM localization could block all oncogenic activity (Baines et al, 2011), which implies NATs are promising lead compounds for treating drug-resistant cancer related to P-glycoprotein (P-gp) mediated drug efflux, and it was found that NATs exhibited significant cytotoxicity toward SW620 Ad300 cell line in which P-gp was overexpressed (Salim et al, 2014). Discovery of Neoantimycins and Their SAR fashion more NATs by biosynthetic engineering (Awakawa et al, 2018) or chemical synthesis (Manaviazar et al, 2016) and investigate the structure-activity relationship (SAR) of NATs against cancer cells. What follows is an account of our chemical and biological studies into NATs

MATERIALS AND METHODS

Mosher Analysis of 5-8

Findings

AND DISCUSSION