Design, Synthesis, and Antiproliferative and CDK2-cyclin a Inhibitory Activity of Novel Flavopiridol Analogues

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2006 Nov 25

PMID 17123821

Citations 6

Authors

Yu Mi Ahn

Lakshminarayana Vogeti

Chun-Jing Liu

Hari K R Santhapuram

Jonathan M White

Veena Vasandani

Lester A Mitscher

Gerald H Lushington

Paul R Hanson

Douglas R Powell

Richard H Himes

Katherine F Roby

Qizhuang Ye

Gunda I Georg

Affiliations

Soon will be listed here.

Abstract

The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. Molecular docking simulations were carried out and these studies suggested a different binding orientation inside the CDK2 binding pocket for these analogues compared to flavopiridol.

Citing Articles

Insight into the synthesis, structure affirmation and catalytic efficiency of divalent and trivalent metal chelates of mandelic acid hydrazone derivative.

El-Ghamry H, Gaber M, Alkhatib F, Al Shareef H, Takroni K, Fathalla S RSC Adv. 2024; 14(42):30673-30686.

PMID: 39324037 PMC: 11423900. DOI: 10.1039/d4ra05769d.

The Pharmacological Implications of Flavopiridol: An Updated Overview.

Joshi H, Tuli H, Ranjan A, Chauhan A, Haque S, Ramniwas S Molecules. 2023; 28(22).

PMID: 38005250 PMC: 10673037. DOI: 10.3390/molecules28227530.

Novel benzo chromene derivatives: design, synthesis, molecular docking, cell cycle arrest, and apoptosis induction in human acute myeloid leukemia HL-60 cells.

El-Hameed R, Mohamed M, Awad S, Hassan B, Khodair M, Mansour Y J Enzyme Inhib Med Chem. 2022; 38(1):405-422.

PMID: 36458403 PMC: 9721423. DOI: 10.1080/14756366.2022.2151592.

Novel benzylidene benzofuranone analogues as potential anticancer agents: design, synthesis and in vitro evaluation based on CDK2 inhibition assays.

Pai A, B S J 3 Biotech. 2022; 12(10):256.

PMID: 36065423 PMC: 9440176. DOI: 10.1007/s13205-022-03312-1.

Design, synthesis and molecular docking of new fused 1-pyrroles, pyrrolo[3,2-]pyrimidines and pyrrolo[3,2-][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors.

Belal A, Abdel Gawad N, Mehany A, Abourehab M, Elkady H, Al-Karmalawy A J Enzyme Inhib Med Chem. 2022; 37(1):1884-1902.

PMID: 35801486 PMC: 9272933. DOI: 10.1080/14756366.2022.2096019.

References

Cohen P . Protein kinases--the major drug targets of the twenty-first century?. Nat Rev Drug Discov. 2002; 1(4):309-15. DOI: 10.1038/nrd773. View

Sedlacek H, Czech J, Naik R, Kaur G, Worland P, Losiewicz M . Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy. Int J Oncol. 2011; 9(6):1143-68. DOI: 10.3892/ijo.9.6.1143. View

Kim S, BRANDSEN J, de Azevedo Junior W . Structural basis for chemical inhibition of CDK2. Prog Cell Cycle Res. 1996; 2:137-45. DOI: 10.1007/978-1-4615-5873-6_14. View

Gray N, Wodicka L, Thunnissen A, Norman T, Kwon S, Espinoza F . Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science. 1998; 281(5376):533-8. DOI: 10.1126/science.281.5376.533. View

Sausville E, Johnson J, Alley M, Zaharevitz D, Senderowicz A . Inhibition of CDKs as a therapeutic modality. Ann N Y Acad Sci. 2000; 910:207-21; discussion 221-2. DOI: 10.1111/j.1749-6632.2000.tb06710.x. View

McGovern S, Shoichet B . Kinase inhibitors: not just for kinases anymore. J Med Chem. 2003; 46(8):1478-83. DOI: 10.1021/jm020427b. View

de Azevedo Jr W, Worland P, Sausville E, Kim S . Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. Proc Natl Acad Sci U S A. 1996; 93(7):2735-40. PMC: 39700. DOI: 10.1073/pnas.93.7.2735. View

Fischer P, Lane D . Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem. 2000; 7(12):1213-45. DOI: 10.2174/0929867003374048. View

Noble M, Endicott J, Johnson L . Protein kinase inhibitors: insights into drug design from structure. Science. 2004; 303(5665):1800-5. DOI: 10.1126/science.1095920. View

10.

Carlson B, Dubay M, Sausville E, Brizuela L, Worland P . Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996; 56(13):2973-8. View

11.

Harper J, Adams P . Cyclin-dependent kinases. Chem Rev. 2001; 101(8):2511-26. DOI: 10.1021/cr0001030. View

12.

Sausville E . Cyclin-dependent kinase modulators studied at the NCI: pre-clinical and clinical studies. Curr Med Chem Anticancer Agents. 2003; 3(1):47-56. DOI: 10.2174/1568011033353560. View

13.

Losiewicz M, Carlson B, Kaur G, Sausville E, Worland P . Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem Biophys Res Commun. 1994; 201(2):589-95. DOI: 10.1006/bbrc.1994.1742. View

14.

Toogood P . Progress toward the development of agents to modulate the cell cycle. Curr Opin Chem Biol. 2002; 6(4):472-8. DOI: 10.1016/s1367-5931(02)00342-3. View

15.

Yang D, Cai S, Zhao Y, Liang H . A new alkaloid from Dysoxylum binectariferum. J Asian Nat Prod Res. 2004; 6(3):233-6. DOI: 10.1080/10286020310001608930. View

16.

Arris C, Boyle F, Calvert A, Curtin N, Endicott J, Garman E . Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J Med Chem. 2000; 43(15):2797-804. DOI: 10.1021/jm990628o. View

17.

Shults M, Imperiali B . Versatile fluorescence probes of protein kinase activity. J Am Chem Soc. 2003; 125(47):14248-9. DOI: 10.1021/ja0380502. View

18.

Sielecki T, Boylan J, Benfield P, Trainor G . Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. J Med Chem. 2000; 43(1):1-18. View

19.

Senderowicz A . Novel small molecule cyclin-dependent kinases modulators in human clinical trials. Cancer Biol Ther. 2003; 2(4 Suppl 1):S84-95. View

20.

Matter W, Brown R, Vlahos C . The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs. Biochem Biophys Res Commun. 1992; 186(2):624-31. DOI: 10.1016/0006-291x(92)90792-j. View