An efficient regioselective synthesis of N-alkylated purine-triazole analogues

Nitrogen rich purine adduct (2) was prepared by reaction of 2,6-dichloro purine (1) with hydrazine hydrate was converted to hybrid purine-triazole ring (4) by a simple cyclisation process (con. HCl & methanol) on reaction with 3-phenoxy benzaldehyde. The regioselectivity of synthesized adducts was carried out by simple spectroscopic techniques i.e. IR, 1H NMR & 13C NMR spectra. These studies gave an idea regarding replacement of chlorine out of C-2 or C-6 position. Novelty was introduced by alkyl substation at N-9 position of imidazole ring and at –NH of triazole ring and a series of 4-chloro-5a,6-dihydro-1,6-dialkylated-8-(3-phenoxyphenyl)-1H-[1,2,4]triazolo[3,4-e]purine (5a-5g) hybrids were synthesized

An efficient regioselective synthesis of N-alkylated purine-triazole analogues

1225-1233Nitrogen rich purine adduct (2) was prepared by reaction of 2,6-dichloro purine (1) with hydrazine hydrate was converted to hybrid purine-triazole ring (4) by a simple cyclisation process (con. HCl & methanol) on reaction with 3-phenoxy benzaldehyde. The regioselectivity of synthesized adducts was carried out by simple spectroscopic techniques i.e. IR, 1H NMR & 13C NMR spectra. These studies gave an idea regarding replacement of chlorine out of C-2 or C-6 position. Novelty was introduced by alkyl substation at N-9 position of imidazole ring and at –NH of triazole ring and a series of 4-chloro-5a,6-dihydro-1,6-dialkylated-8-(3-phenoxyphenyl)-1H-[1,2,4]triazolo[3,4-e]purine (5a-5g) hybrids were synthesized

The analog of cGAMP, c-di-AMP, activates STING mediated cell death pathway in estrogen-receptor negative breast cancer cells

Immune adaptor protein like STING/MITA regulate innate immune response and plays a critical role in inflammation in the tumor microenvironment and regulation of metastasis including breast cancer. Chromosomal instability in highly metastatic cells releases fragmented chromosomal parts in the cytoplasm, hence the activation of STING via an increased level of cyclic dinucleotides (cDNs) synthesized by cGMP-AMP synthase (cGAS). Cyclic dinucleotides 2’ 3’-cGAMP and it's analog can potentially activate STING mediated pathways leading to nuclear translocation of p65 and IRF-3 and transcription of inflammatory genes. The differential modulation of STING pathway via 2’ 3’-cGAMP and its analog and its implication in breast tumorigenesis is still not well explored. In the current study, we demonstrated that c-di-AMP can activate type-1 IFN response in ER negative breast cancer cell lines which correlate with STING expression. c-di-AMP binds to STING and activates downstream IFN pathways in STING positive metastatic MDA-MB-231/MX-1 cells. Prolonged treatment of c-di-AMP induces cell death in STING positive metastatic MDA-MB-231/MX-1 cells mediated by IRF-3. c-di-AMP induces IRF-3 translocation to mitochondria and initiates Caspase-9 mediated cell death and inhibits clonogenicity of triple-negative breast cancer cells. This study suggests that c-di-AMP can activate and modulates STING pathway to induce mitochondrial mediated apoptosis in estrogen-receptor negative breast cancer cells

Regioselective synthesis of triazolo[3,4-e]purine derivatives and their anti-cancer activity against NCI-60 cell-lines

Introduction: Due to the vast medicinal importance of purine nucleoside, a hybrid molecule of triazole with purine ring might explode a lead molecule in the pharma sector and based on the last decade’s studies suggested that the nitrogen-rich molecules possess a wide range of medicinal importance.Aim: Due to the vast application of purine nucleoside itself in the field of cancer research, we synthesized triazolo[3,4-e]purines and screened them for their anti-cancer study against NCI-60 cell lines by the protocol used by NIH.Materials and methods: The targeted molecules, 4-chloro-5a,6-dihydro-8-substitutedphenyl-1H-[1,2,4]triazolo[3,4-e]purine derivatives (4a-4h) were synthesized in a two-step procedure by nucleophilic substitution (SN) at C-2 chlorine followed by formation of the triazole ring by acid-catalyzed reaction in the polar protic solvent.Results: It was observed that the regioselective approach followed in C-2 chlorine replacement instead of C-6 chlorine during SN reaction. One-dose response of selected three molecules (4a, 4b, and 4c) showed that 4b (K-562: 64.47 µM & SR: 63.38 µM; mean GI50: 99.09 µM) was found to be more potent than 4a and 4c.Conclusions: We have described in this study the general synthetic method for triazolo[3,4-e]purines as an innovative class of potential anticancer agents. The dose-response curve in the sense of mean GI50 for three compounds across all 60 cell lines, 4b can be served as lead after necessary modification