Novel 1H-Pyrrolo[2,3-b]pyridine Derivative Nortopsentin Analogues: Synthesis and Antitumor Activity in Peritoneal Mesothelioma Experimental Models

Abstract

In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr(34)-phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well-tolerated doses, and two complete responses were observed in each treatment group.

An acyl-Claisen/Paal-Knorr approach to fully substituted pyrroles

“…Compounds containing the pyrrole core have been found to possess antitumoral, antimalarial, antifungal, antibacterial and anti-HIV activity and as such, they represent interesting lead compounds for drug development. [1][2][3][4][5][6] The pharmaceutical potential of pyrrolic compounds is exemplified by the HMG-CoA reductase inhibitor atorvastatin, which has become one of the best-selling pharmaceutical products since its introduction to the global market in 1990. [7][8][9] Pyrrolic compounds continue to enter the pharmaceutical market and include molecules such as the receptor tyrosine kinase inhibitor sunitinib, approved in 2011 for the treatment of advanced neuroendocrine tumours of the pancreas.…”

Synthesis of substituted isoindolo[2,1-a]quinoxalin-6-yl–amino and 6-imino-5-yl thiourea derivatives

“…Quinoxalinylethylpyridylthioureas (QXPTs) of type 1 and 2 ( Figure 2) represent another class of NNRTIs; many compounds showed a potent activity against both HIV-1 wild-type RT and various HIV-1 mutants HIV-1 RT. 16 Considering the good experience reached in the course of our researches on polycyclic nitrogen systems, bearing pyrrole, [17][18][19][20][21][22][23][24] indole, [25][26][27][28][29][30][31][32][33][34][35] isoindole 36-38 and indazole …”

Synthesis, characterization and cytotoxic investigations of novel bis(indole) analogues besides antimicrobial study

“…Due to the interesting biological activities, different analogues of the marine nortopsentins have been synthesized in which the imidazole moiety of the nortopsentin was replaced by five-or six-membered heterocyclic rings such as thiazole Carbone et al, 2015Carbone et al, , 2013Carbone et al, 2014), pyrazinone (Jiang and Gu, 2000), pyrimidines, pyrazines , thiophenes (Diana et al, 2007a), pyridines , pyrazoles (Diana et al, 2007b) and 1,2,4-thiadiazoles which were reported for their cytotoxicity against several cancer cell lines.…”