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

Abstract

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN. Especially, compounds 13r and 13p (IC 0.38 and 0.85μM, respectively) displayed the greatest cytotoxicity against the MDR KB-VIN cell line and merit further development into preclinical and clinical drug candidates for treating cancer, including MDR phenotype.

Piperazine skeleton in the structural modification of natural products: a review

“…Moreover, the potency of the compounds with the aromatic substituents (R1) depended significantly upon the nature of the R2 substituent on the aromatic ring. Compound 58 (Figure 29) displayed the highest cytotoxicity against the MDR KB-VIN cell line (IC 50 ¼ 0.38 mM), while irinotecan lost activity completely against KB-VIN (IC 50 > 20 mM) 85 . SAR study suggested that both aromatic and aliphatic substituents on the sulphonyl-piperazinyl side chain at C-7 can promote potency to some extent, while selected variations of these substituents can greatly affect the activity.…”

Design and synthesis of novel 7-[(N-substituted-thioureidopiperazinyl)-methyl]-camptothecin derivatives as potential cytotoxic agents

“…The starting CPT was isolated from the Chinese medicinal plant C. acuminata and purified before being used. The key intermediates 10, 11 and 12 were synthesized using the procedure we reported previously (Yang et al 2017). Their structures were confirmed by direct comparison with an authentic sample and previously reported spectroscopic data.…”

Lead/Drug Discovery from Natural Resources

“…It is interesting that a number of bisindole alkaloids (taburnaemine A, etc., Table 1 ) isolated from Tabernaemontana corymbosa showed antiproliferative activity (IC 50 2.6–9.8 μM) against several human cancer cell lines, including A-549, the triple-negative breast cancer (TNBC) cell line (MDA-MB-231, a highly metastatic cancer that lacks efficient targeted chemotherapy), ER + /PR + breast cancer (MCF-7), KB and KB-VIN cells [ 37 ]. Camptothecin derivatives 4 and 5 ( Figure 2 , Table 2 ) were reported to display cytotoxicity against the MDR KB-VIN and parental KB tumor cell lines, while irinotecan lost its activity completely against KB-VIN [ 58 ]. In a molecular docking model, a 20-sulfonylamidine derivative of camptothecin interacted with Topo I-DNA via a different binding mode from camptothecin and irinotecan [ 59 ].…”

“…NR: not reported in the original paper. A2780 (human ovarian cancer), A549 (lung cancer), BGC-823 (human gastric cancer cell line), Hep3B (hepatocellular carcinoma, HCC), HepG-2 (liver hepatocellular cells), HCT-116 (human colon cancer), KB (nasopharyngeal carcinoma), KB-vin (vincristine resistant KB subline), MCF (Michigan Cancer Foundation-7), MDA-MB-231(human breast carcinoma cell line), NCI-H1650 (non-small-cell carcinoma) [ 33 , 35 , 58 , 60 , 61 , 62 , 63 , 64 , 67 , 68 , 69 ].…”