Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor

Aware, Valmik; Gaikwad, Nitin V; Chavan, Sambhaji; Manohar, Sonal M; Bose, Julie; Khanna, Smriti; B-Rao, Chandrika; Dixit, Neeta; Singh, Kishori Sharan; Damre, Anagha; Sharma, Rajiv; Patil, S. K.; Roychowdhury, Abhijit

doi:10.1016/j.ejmech.2014.12.053

Cited by 19 publications

(6 citation statements)

References 30 publications

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“…A series of novel 4-pyrazolecyclopentylpyrimidines were prepared and evaluated in vitro as IGF-1R tyrosine kinase inhibitors. Compound 273 was found to be most active, with an IC 50 value of 10 nM [ 178 ]. Several new series of benzenesulfonamide derivatives incorporating pyrazole were prepared by Ibrahim et al and screened for anti-tumor activity against the metalloenzyme carbonic anhydrase and human isoforms hCA I, II, IX and XII.…”

Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.

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Section: Pharmacological Activitiesmentioning

confidence: 99%

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

et al. 2018

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“…Several new analogues were prepared with modifications at the C2 position of the pyrimidine ring (B-ring), as shown in Scheme . Using methods described in the literature, , we synthesized the key precursor 4-chloro-2-(methylthio)-6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine (compound 5 ) from hydroxy pyrimidine (compound 4 ) and ethyl 2-oxocyclopentanecarboxylate (compound 2 ). Compound 5 was coupled with 4-methoxy-2-nitroaniline (compound 6 ) in dry isopropyl alcohol (IPA) in the presence of a catalytic amount of HCl (3–4 drops) to obtain 2-methylthio 4-(4-methoxy-2-nitrophenyl) amino pyrimidine (compound 7 ) in good yield .…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Pyrimidine Dihydroquinoxalinone Derivatives as Tubulin Colchicine Site-Binding Agents That Displayed Potent Anticancer Activity Both In Vitro and In Vivo

Pochampally

Hartman

Wang

et al. 2023

ACS Pharmacol. Transl. Sci.

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Polymerization of tubulin dimers to form microtubules is one of the key events in cell proliferation. The inhibition of this event has long been recognized as a potential treatment option for various types of cancer. Compound 1e was previously developed by our team as a potent inhibitor of tubulin polymerization that binds to the colchicine site. To further improve the potency and therapeutic properties of compound 1e, we hypothesized based on the X-ray crystal structure that modification of the pyrimidine dihydroquinoxalinone scaffold with additional hetero-atom (N, O, and S) substituents could allow the resulting new compounds to bind more tightly to the colchicine site and display greater efficacy in cancer therapy. We therefore synthesized a series of new pyrimidine dihydroquinoxalinone derivatives, compounds 10, 12b−c, 12e, 12h, and 12j−l, and evaluated their cytotoxicity and relative ability to inhibit proliferation, resulting in the discovery of new tubulin-polymerization inhibitors. Among these, the most potent new inhibitor was compound 12k, which exhibited high cytotoxic activity in vitro, a longer half-life than the parental compound in liver microsomes (IC 50 = 0.2 nM, t 1/2 = >300 min), and significant potency against a wide range of cancer cell lines including those from melanoma and breast, pancreatic, and prostate cancers. High-resolution X-ray crystal structures of the best compounds in this scaffold series, 12e, 12j, and 12k, confirmed their direct binding to the colchicine site of tubulin and revealed their detailed molecular interactions. Further evaluation of 12k in vivo using a highly taxane-resistant prostate cancer xenograft model, PC-3/TxR, demonstrated the strong tumor growth inhibition at the low dose of 2.5 mg/kg (i.v., twice per week). Collectively, these results strongly support further preclinical evaluations of 12k as a potential candidate for development.

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“…Some pyrazole‐based drugs are depicted in Figure . Pyrazole derivatives show anticancer activity due to their inhibition of various targets such as EGFR , IGF‐1R , tubulin , B‐raf , mTOR , HDAC , ALK , topoisomerase II , JAK2 , ROS 1 , among others. Hence, incorporation of the pyrazole moiety is an important synthetic strategy in rational drug development process.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents

Abdelgawad

Ismail

Hekal

et al. 2019

Journal of Heterocyclic Chem

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1,3‐Diphenylpyrazole‐4‐carboxylaldehyde and o‐hydroxyacetophenone were exploited as starting materials for the synthesis of novel substituted chalconated pyrazole derivative. The proclivity of this compound towards carbon and nitrogen nucleophiles such as malononitrile, diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate, semicarbazide, thiosemicarbazide, and hydroxylamine has been investigated. The structures of all synthesized compounds were ascertained by analytical and spectral data. The antitumor activity of the target synthesized compounds was tested against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2 and mammary gland breast MCF‐7.

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Cyclopentyl-pyrimidine based analogues as novel and potent IGF-1R inhibitor

Cited by 19 publications

References 30 publications

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Design, Synthesis, and Biological Evaluation of Pyrimidine Dihydroquinoxalinone Derivatives as Tubulin Colchicine Site-Binding Agents That Displayed Potent Anticancer Activity Both In Vitro and In Vivo

Design, Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents

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