دورية أكاديمية
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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.

التفاصيل البيبلوغرافية
العنوان: 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.
المؤلفون: Pochampally S; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Hartman KL; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Wang R; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Wang J; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Yun MK; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Parmar K; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Park H; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Meibohm B; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., White SW; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States., Li W; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States., Miller DD; Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
المصدر: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2023 Mar 22; Vol. 6 (4), pp. 526-545. Date of Electronic Publication: 2023 Mar 22 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101721411 Publication Model: eCollection Cited Medium: Internet ISSN: 2575-9108 (Electronic) Linking ISSN: 25759108 NLM ISO Abbreviation: ACS Pharmacol Transl Sci Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Chemical Society, [2018]-
مستخلص: 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.
Competing Interests: The authors declare no competing financial interest.
(© 2023 American Chemical Society.)
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معلومات مُعتمدة: R01 CA193609 United States CA NCI NIH HHS; R01 CA240447 United States CA NCI NIH HHS; R01 CA148706 United States CA NCI NIH HHS; S10 OD010678 United States OD NIH HHS; S10 RR026377 United States RR NCRR NIH HHS
تواريخ الأحداث: Date Created: 20230421 Latest Revision: 20240323
رمز التحديث: 20240323
مُعرف محوري في PubMed: PMC10111625
DOI: 10.1021/acsptsci.2c00108
PMID: 37082747
قاعدة البيانات: MEDLINE
الوصف
تدمد:2575-9108
DOI:10.1021/acsptsci.2c00108