Synthesis and anticancer activity of multisubstituted purines and xanthines with one or two propynylthio and aminobutynylthio groups

Abstract

A synthesis of new 2,6-disubstituted and 2,6,8-trisubstituted 7-methylpurines as well as 8-substituted 3,7-dimethylxanthines containing a triple bond chain have been worked out. Purinethiones and xanthinethiones were converted into propynylthio derivatives, which were then further transformed via a Mannich reaction into aminobutynylthio derivatives (amine = pyrrolidine, piperidine, morpholine, and diethylamine). The products thus obtained represent various types of the purine and xanthine structure: 8-mono-, 2,6- and 6,8-dipropynylthio, 6- and 8-monoaminobutynylthio, 2,6- and 6,8-diaminobutynylthio derivatives. All of these compounds were tested for their anticancer activity against human glioblastoma SNB-19, human adenocarcinoma MDA-MB-231, and melanoma C-32 cell lines. The anticancer activity depends on the nature of the substituent and its localization in the purine and xanthine framework. Generally, compounds possessing two alkynylthio groups (propynylthio or aminobutynylthio) were more active than those possessing only one group. Some compounds exhibited stronger or similar anticancer activity to cisplatin. All compounds were also tested for their cytotoxic activity against normal human fibroblasts (HFF-1). The most promising anticancer compounds were found to be 2,6-dipropynylthio-7-methylpurine 4, 2-chloro-6,8-dipropynylthio-7-methylpurine 14, and 2-chloro-6,8-di(N-morpholinylbutynylthio)-7-methylpurine 15c acting selectively on glioblastoma SNB-19, melanoma C-32, and adenocarcinoma MDA-MB-231 with the IC50 = 0.07–4.08 μg/mL.

Crocodylus porosus: a potential source of anticancer moleculesCrocodylus porosus: a potential source of anticancer molecules

“…Purine derivatives such as 2,6-dipropynylthio-7-methylpurine 4, 2-chloro-6,8-dipropynylthio-7-methylpurine 14, and 2-chloro-6,8-di(N-morpholinylbutynylthio)-7-methylpurine exhibited anticancer activity against glioblastoma SNB-19, melanoma C-32 and adenocarcinoma MDA-MB-231 50 …”

Imidazoles as Potential Anticancer Agents: An Update on Recent Studies

“…Kowalska et al tested the anticancer activity of multisubstituted purine and xanthine derivatives against SNB-19, MDA-MB-231, and C32 cell lines and also counter-screened these compounds against normal HFF-1 cells [ 207 ]. The target compounds possessed a range of activities against the four cell lines tested.…”

“…By comparison, doxorubicin displayed an EC 50 value of 1.4 µM against both CCRF-CEM and MCF-7 cells. These proxyphylline analogs were also tested for antifungal activity against Candida albicans, with compounds 270 and 269 exhibiting the best antifungal activity.Kowalska et al tested the anticancer activity of multisubstituted purine and xanthine derivatives against SNB-19, MDA-MB-231, and C32 cell lines and also counter-screened these compounds against normal HFF-1 cells[207]. The target compounds possessed a range of activities against the four cell lines tested.…”

Novel Bis- and Mono-Pyrrolo[2,3-d]pyrimidine and Purine Derivatives: Synthesis, Computational Analysis and Antiproliferative Evaluation

“…Over the past years, some pyrrolo [2,3-d]pyrimidine derivatives were identified as inhibitors of Mer receptor and Src non-receptor tyrosine kinases, isoform of protein kinase B (Akt), mitotic checkpoint kinase (Mps1), Janus kinase 2 (JAK2), and phosphoinositide 3 kinase (PI3K) with promising anticancer activity [25][26][27][28][29][30][31][32][33]. Design strategy in development of purine derivatives as cytostatic agents for kinase inhibition revealed that introduction of cyclic amines improved the activity by forming an additional hydrogen bond to kinase hinge [9,34,35]. In addition, prevalence of halogenated drugs showed that halogen bonds contribute to the stability of protein-ligand complexes [36].…”