Open AccessTotal Synthesis and Conformational Analysis of Naturally Occurring Lipovelutibols along with Lead Optimization of Lipovelutibol D
Author(s) -
Varun Pratap Singh,
Anup Singh Pathania,
Shrestha Sharma,
Fayaz Malik,
Anil Kumar,
Deepika Singh,
Ram A. Vishwakarma
Publication year - 2021
Publication title -
acs omega
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.779
H-Index - 40
ISSN - 2470-1343
DOI - 10.1021/acsomega.0c04038
Subject(s) - chemistry , cytotoxicity , stereochemistry , cytotoxic t cell , lead compound , intramolecular force , cancer cell lines , two dimensional nuclear magnetic resonance spectroscopy , cancer cell , biochemistry , cancer , biology , in vitro , genetics
Four lipopeptaibols, namely, lipovelutibols A-D, were recently isolated from psychrotrophic fungus Trichoderma velutinum and reported to have significant cytotoxic activity against HL-60, MDA-MD-231, A549, and LS180 cancer cell lines. In the present study, these peptides were synthesized in a solution using a segment condensation approach. The conformational analysis of these peptides carried out using CD spectrophotometry revealed the formation of 3 10 -helix, and the NMR-VT experiments showed intramolecular hydrogen bonding for NH-5, NH-6, and NH-7. Lipovelutibol D showed potent cytotoxic activity and was chosen for lead optimization. It involved N- and C - terminal truncation, N- and C - terminal modification, random deletion, l/d configuration replacement, and other synthetic analogues. These were tested against various breast cancer cell lines. The C-terminal aldehyde analogue resulting from lead optimization of lipovelutibol D was found to have almost twofold enhanced cytotoxicity against MDA-MB-231 breast cancer cell lines.