Singh Varun Pratap, Pathania Anup Singh, Sharma Sonia, Malik Fayaz Ahmed, Kumar Anil, Singh Deepika, Vishwakarma Ram A
Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
School of Biotechnology, Faculty of Sciences, Shri Mata Vaishno Devi University, Katra, Jammu and Kashmir 182320, India.
ACS Omega. 2021 Feb 26;6(9):6070-6080. doi: 10.1021/acsomega.0c04038. eCollection 2021 Mar 9.
Four lipopeptaibols, namely, lipovelutibols A-D, were recently isolated from psychrotrophic fungus 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-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 Cterminal truncation, N- and Cterminal 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.
最近从嗜冷真菌中分离出四种脂肽博来霉素，即脂博来霉素A - D，并报道它们对HL - 60、MDA - MD - 231、A549和LS180癌细胞系具有显著的细胞毒性活性。在本研究中，这些肽采用片段缩合方法在溶液中合成。使用圆二色光谱法对这些肽进行的构象分析显示形成了α - 螺旋，核磁共振变温实验表明NH - 5、NH - 6和NH - 7存在分子内氢键。脂博来霉素D表现出强大的细胞毒性活性，并被选用于先导化合物优化。这涉及N端和C端截短、N端和C端修饰、随机缺失、l/d构型替换以及其他合成类似物。对这些进行了针对各种乳腺癌细胞系的测试。发现由脂博来霉素D的先导化合物优化产生的C端醛类似物对MDA - MB - 231乳腺癌细胞系的细胞毒性增强了近两倍。
