Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Design, Synthesis and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines

Xiaolin Li
,
Tianrong Xun
,
Huayan Xu
,
Xiaoyan Pang
,
Bin Yang
,
Junfeng Wang
ORCID logo ,
Xuefeng Zhou
ORCID logo ,
Xiuping Lin
,
Suiyi Tan
* ,
Yonghong Liu
* ORCID logo ,
Shengrong Liao
* ORCID logo
Version 1 : Received: 27 April 2023 / Approved: 27 April 2023 / Online: 27 April 2023 (07:11:44 CEST)

A peer-reviewed article of this Preprint also exists.

Li, X.; Xun, T.; Xu, H.; Pang, X.; Yang, B.; Wang, J.; Zhou, X.; Lin, X.; Tan, S.; Liu, Y.; Liao, S. Design, Synthesis, and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines. Mar. Drugs 2023, 21, 325. Li, X.; Xun, T.; Xu, H.; Pang, X.; Yang, B.; Wang, J.; Zhou, X.; Lin, X.; Tan, S.; Liu, Y.; Liao, S. Design, Synthesis, and Anticancer Activity of Novel 3,6-Diunsaturated 2,5-Diketopiperazines. Mar. Drugs 2023, 21, 325.

Abstract

Based on the marine natural products piperafizine B, X334 and our previously reported compound 4m, fourteen novel 3,6-diunsaturated 2,5-diketopiperazine (2,5-DPK) derivatives (1-2, 4-6, 8-16), together with two known ones (3 and 7), were designed and synthesized as anticancer agents against cell lines A549 and Hela. The MTT assay results showed that the derivatives 6, 8-12 and 15 had moderate to good anticancer capacities with the IC50 values ranging from 0.7 to 8.9 μM. Among them, compound 11 with naphthalen-1-ylmethylene and 2-methoxybenzylidene functions at the 3- and 6-positions of 2,5-DPK ring, respectively, displayed good inhibitory activities to both cancer cells A549 (IC50 = 1.2 μM) and Hela (IC50 = 0.7 μM). It could also induce apoptosis and obviously block the cell cycle progression at G2/M phase in both cells at 1.0 μM. The electron withdrawing functions might not be favorable for the derivatives with high anticancer activities. Additionally, compared to piperafizine B and X334, these semi-N-alkylated derivatives have high liposolubilities (> 1.0 mg•mL-1). Compound 11 can be further developed aiming to the discovery of novel anticancer candidate.

Keywords

2,5-diketopiperazine derivative; intermolecular bond; liposolubility; electron property; anticancer

Subject

Medicine and Pharmacology, Medicine and Pharmacology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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