Synthesis and preliminary evaluation of novel alkyl diamine linked bivalent β-carbolines as angiogenesis inhibitors

Abstract

A series of novel bivalent β-carbolines were synthesized and evaluated as potent angiogenesis inhibitors.

Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents

“…The syntheses of compounds 8a – ab are depicted in Scheme 1, Scheme 2 and Scheme 3. Monovalent β-carbolines 6a – l and 7a – l were synthesized according to previously published methods [39,47,48]. Using L-tryptophan as starting material, the tetrahydro-β-carboline skeleton ( 2a – g ) was constructed via Pictet–Spengler cyclization.…”

“…Then, the obtained carboxylic acid 2 reacted with thionyl chloride and ethanol to form ethyl ester 3 , which subsequently reacted with sulfur in xylene to afford compounds 4a – g . Then compounds 4a – g were reduced to their corresponding alcohols by lithium borohydride (LiBH 4 ) in dry THF to provide compounds 5a – g , and further oxidized by MnO 2 in CH 3 CN to afford the key intermediates, the 3-carboxaldehyde derivatives 6a – g [39]. Alternatively, refluxing of compounds 4a – g with 80% hydrazine hydrate in ethanol gave the other key intermediates, hydrazides 7a – g [39] (see Scheme 1).…”

“…To determine in vivo anti-angiogenic activity of heterobivalent β-carbolines, a CAM assay was performed as previously described [39]. In brief, five-day-old fertilized chicken eggs were purchased from a local hatchery.…”

“…So our group reported the synthesis, in vitro evaluation, in vivo efficacies, and SARs of the new homobivalent β-carbolines and heterobivalent β-carbolines with alkyl or alkylamino spacers in positions 1, 3, 7, and 9 of the β-carboline nucleus (Figure 2) [39,40,41,42]. In these homobivalent β-carbolines, 1-Methyl-9-[4-(1-methyl-β-carboline-9-yl)butyl]-β-carboline (B-9-3) [43,44] exhibited potent antitumor activity.…”

“…The pharmacological mechanisms showed that B-9-3 selectively induces apoptosis of endothelial cells, in part through disruption of VEGF-A/VEGFR2 signaling [45], and also acts on the TGF-β signaling pathway [46]. Compounds B-3 [39] and B-4 [40] exhibited significant angiogenesis inhibitory effects in chicken chorioallantoic membrane (CAM) assay, and the anti-angiogenetic potency was comparable or more potent with the drug Endostar.…”