Synthesis and anticancer activities of novel (tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4-yl)-pyrolidine-2-carboxylic acid derivatives

Pavase, Laxmikant S.; Mane, Dhananjay V.

doi:10.1007/s00044-016-1692-x

Cited by 14 publications

(4 citation statements)

References 19 publications

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“…Isosteric replacement of -NH with (-S-) has literature precedence in improving antiproliferative and microtubule depolymerizing activities [ 27 ]. Moreover, pharmacological applications of 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidines have been extensively illustrated in various reports in the literature [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. In addition, the lead tricyclic compounds and the proposed target compounds incorporate a p-methoxyphenyl substitution akin to colchicine and CA-4 ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

et al. 2022

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A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and SNAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC50 values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC50 values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI50 of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

et al. 2022

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“…Pyrrolidines, organic nitrogenous bases, have a broad range of biological effects, including neurological (Katavic et al, 2007), antiviral (Gaudernak et al, 2002), antibacterial (Meiyazhagan et al, 2015), and anticancer (Arun et al, 2014;Pavase and Mane, 2016). Moreover, the pro-oxidant activity of pyrrolidine derivates has also been described (Onishi et al, 2012;Riera et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress mediated by pyrrolidine SS13 is involved in autophagic cell death induction in colorectal cancer cells

Nosálová

Majirská

Kešeľáková

et al. 2023

Preprint

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Pyrrolidines, nitrogenous organic compounds, are among the most intensively studied substances because of their antibacterial, antiviral, neurological, and promising antitumor effects. This study aimed to evaluate the pro-oxidative properties of SS13 on human colorectal carcinoma cell lines (HCT116 and Caco-2) using flow cytometry, western blot, fluorescence microscopy and qRT-PCR. Pyrrolidine SS13 induced the accumulation of reactive oxygen and nitrogen species in both cell lines. N-acetyl cysteine and Trolox, known antioxidants, reduced the increased levels of free radicals mediated by SS13 treatment. Moreover, modulation of both superoxide dismutase isoenzymes (SOD1, SOD2) was confirmed by western blot analysis and qRT-PCR. Oxidative stress was also associated with DNA damage response system activation and modulation of stress/survival pathways. We demonstrated for the first time that pyrrolidine SS13 is involved in the induction of autophagy by increasing the levels of autophagic markers (p-AMPK, p-ULK, LC3I/II, and ATG7). In addition, a significant decreasing effect on p62 protein levels was observed in both cell lines. Finally, chloroquine, an autophagy inhibitor, increased cell survival and suppressed the cytotoxic effect of SS13 in HCT116 and Caco-2 cells, indicating the involvement of SS13 in autophagy-mediated cell death. Taken together, our results suggest that oxidative stress and autophagy contribute to the antiproliferative effect of pyrrolidine SS13 on colorectal cancer cells.

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“…The main part of our research has been devoted to synthetic methods containing the pyrazole nucleus, as a pharmacophoric moiety for potential drugs. Also, sulfonamides and hydrazide with their heterocyclic analogs showed evidence of diverse biological activities including anticancer and anti‐inflammatory properties. In particular, the pyrazole nucleus represents a very attractive scaffold to obtain new molecules endowed with anti‐inflammatory activities .…”

Section: Introductionmentioning

confidence: 99%

Anti‐inflammatory Exploration of Sulfonamide Containing Diaryl Pyrazoles with Promising COX‐2 Selectivity and Enhanced Gastric Safety Profile

Pavase

Mane

Baheti³

2018

Journal of Heterocyclic Chem

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in Wiley Online Library (wileyonlinelibrary.com).Novel sulfonamide containing diaryl pyrazoles were synthesized and were subsequently tested for their in vitro cyclooxygenase inhibitory assay. Compounds that showed promising in vitro COX-2 IC 50 values and selectivity indices were then evaluated for their in vivo anti-inflammatory inhibition assay using standard carrageenan-induced rat paw edema method. Two promising inhibitors were evaluated for ulcerogenic liability. X-ray crystal structure of COX-2 was taken from PDB entry COX-2 (3LN1) having a resolution of 2.80 Å (Angstroms). Structural preparations for docking studies were accomplished using protein preparation wizard in Maestro 9.0. Compound 10b displayed reasonable COX-2 inhibition (COX-2 IC 50 = 0.52 μM) and COX-2 selectivity index (SI = 10.73) when compared with celecoxib (COX-2 IC 50 = 0.78 μM) and (SI = 9.51). In vivo anti-inflammatory studies demonstrated 64.28% inhibition for 10b in comparison with the 57.14% for that of celecoxib itself. The results of ulcerogenic liability were also found comparable with standard celecoxib. Molecular docking studies revealed that all the designed molecules showed good interactions with receptor active site with glide scores in the range À13.130 to À10.624. 69%); mp = 192-194°C; 1 H NMR (DMSO-d 6, 400 MHz) δ 7.84 (d, 2H, J = 8.4 Hz, Ar─H), 7.49-7.51 (m, 4H, Ar─H), 7.38-7.39 (m, 2H, Ar─H), 7.27-7.29 (m, 2H, Ar─H), 7.13 (s, 1H, Pyrazole-H), 4.34 (q, 2H, J = 6.8 Hz, ─OCH 2 ─CH 3 ), 1.30 (t, 3H, ─OCH 2 ─CH 3, J = 7.2 Hz); ES-MS: m/z 372.2 (M + H) + . 4-(3-Hydrazinocarbonyl-5-phenylpyrazol-1-yl)benzenesulfonamide (9).To a suspension of ester intermediate (10 g, 269 mmol) 8 in ethanol (50 mL) was added hydrazine hydrate (6.72 g, 134 mmol) and refluxed the reaction mixture for 6 h. Reaction mixture becomes clear at the completion of the reaction under reflux.

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Synthesis and anticancer activities of novel (tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidine-4-yl)-pyrolidine-2-carboxylic acid derivatives

Cited by 14 publications

References 19 publications

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

Oxidative stress mediated by pyrrolidine SS13 is involved in autophagic cell death induction in colorectal cancer cells

Anti‐inflammatory Exploration of Sulfonamide Containing Diaryl Pyrazoles with Promising COX‐2 Selectivity and Enhanced Gastric Safety Profile

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