Synthesis and In Vitro Antitumor Activity of Novel Ring D Analogues of the Marine Pyridoacridine Ascididemin: Structure−Activity Relationship

Abstract

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.

Synthesis and Structure–Activity Relationship of Cytotoxic Marine Cyclodepsipeptide IB‐01212 Analogues

“…), 4) chemical synthesis, [19] 5) structure-activity relationship (SAR) studies for drug optimization, [20,21] and finally, 6) assurance of a homogeneous supply of the compound for preclinical and clinical trials. [22,23] Each of these stages is crucial in the development of a drug.…”

Pyridoacridines in the 21st Century

“…The quinoline‐5,8‐dione employed in Scheme was also used in the synthesis of non‐natural analogues 117 (Scheme ) . The quinone was treated with various ortho ‐aminoacetophenones 114 to provide variation in the benzene ring, and the products 115 closed to tetracycles 116 with strong acid.…”

A mini review on pyridoacridines: Prospective lead compounds in medicinal chemistry

“…In a study conducted by Delfourne and co-workers in [45] , ascididemin analogues were synthesized and evaluated for their cytotoxic potential by MTT assay. Some ascididemin analogues (ring D-modified) appeared to be more cytotoxic than the reference compound ascididemin ( Table 2 ).…”

“…Some ascididemin analogues (ring D-modified) appeared to be more cytotoxic than the reference compound ascididemin ( Table 2 ). Furthermore, it was reported that substitution at R 1 and R 3 does not have much influence on cytotoxic activity [45] .…”

“…Debnath and co-workers [46] , carried out QSAR studies on the above mentioned ascididemin analogues reported by Delfourne et al [45] and emphasized that the presence of an electron withdrawing substituent with higher molar refractivity value and the presence of NHR (R is hydrogen or alkyl group) at R 1 and R 3 positions, respectively, favoured the anti-tumour activity of ascididemin analogues [ Fig. 3 ] [45,46] .…”