Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

Abstract

In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogues showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.

DNA Topoisomerase 1 Structure-BASED Design, Synthesis, Activity Evaluation and Molecular Simulations Study of New 7-Amide Camptothecin Derivatives Against Spodoptera frugiperda

“…Among the camptothecin derivatives we designed, some compounds, such as 4j and 4m could form strong hydrogen bonds with the insect Top1. Interestingly, the amino acid residues Asn352 and Lys436 in Hs Top1, which are equivalent to Asn518 and Lys602 residues in sf Top1, may also form H-bond interactions with camptothecin derivatives to stabilize the ternary complex (Song et al, 2016 ). In different organisms, these two amino acid residues behave very conservatively, and they are located in the active pocket of the protein.…”

Synthesis, antitumor activity and pharmacokinetic study of 10‐propionyloxy camptothecin in rats

“…Although this compound has prominent antitumor effects toward a wide range of experimental tumors, severe toxicity as tested both in animal experiments and clinical trials hamper its use as an anticancer drug clinically (Garcia-Carbonero & Supko, 2002). Over the past decades, thousands of CPT derivatives have been synthesized by different groups and the main CPT derivatives include the marketed drugs topotecan and irinotecan, both using HCPT as the intermediate, along with several other derivatives at various stages of preclinical or clinical development, such as gimatecan, CKD-602 and BNP-1350 (Song et al, 2016). Over the past decades, thousands of CPT derivatives have been synthesized by different groups and the main CPT derivatives include the marketed drugs topotecan and irinotecan, both using HCPT as the intermediate, along with several other derivatives at various stages of preclinical or clinical development, such as gimatecan, CKD-602 and BNP-1350 (Song et al, 2016).…”

“…10-Hydroxycamptothecin (HCPT), possesses better activities against the cell line 9 KB (human nasopharyngeal carcinoma) in vitro and P388 lymphocytic leukemia system in vivo, and is currently clinically used against gastric carcinoma, hepatoma, leukemia and tumors of head and neck in China (Pu et al, 2009;, although toxicity still presents a serious obstacle to practical use. Over the past decades, thousands of CPT derivatives have been synthesized by different groups and the main CPT derivatives include the marketed drugs topotecan and irinotecan, both using HCPT as the intermediate, along with several other derivatives at various stages of preclinical or clinical development, such as gimatecan, CKD-602 and BNP-1350 (Song et al, 2016). Previous studies have noted that the substituents at the 10position of CPT can improve the antitumor activity, as well as increasing E-ring stability (Zhao et al, 2014).…”

Design, synthesis, and cytotoxic activity of novel 7-substituted camptothecin derivatives incorporating piperazinyl-sulfonylamidine moieties

“…22,23 Among these derivatives, compound 9 is attractive as a potential candidate for anticancer chemotherapy and the modification with sulfonylamidine-substituted side chains may over-come some limitations of 1 . These encouraging results prompted us to further extend our investigation by synthesizing a novel series of 7-piperazinyl-sulfonylamidine-CPT derivatives.…”