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Literature DB >> 20045644

Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.

Ji-Hye Kang¹, Yerim Kim, Shin-Hye Won, Song-Kyu Park, Chang Woo Lee, Hwan-Mook Kim, Nancy E Lewin, Nicholas A Perry, Larry V Pearce, Daniel J Lundberg, Robert J Surawski, Peter M Blumberg, Jeewoo Lee.

Abstract

A series of DAG-lactones with polar 3-alkylidene substituents have been investigated as PKC-alpha ligands and antitumor agents. Extensive analysis of structure-activity relationships for the 3-alkylidene chain revealed that polar groups such as ether, hydroxyl, aldehyde, ester, acyloxy, and amido were tolerated with similar binding affinities and reduced lipophilicities compared to the corresponding unsubstituted alkylidene chain. Among the derivatives, compounds 5, 6 and 8 with an ether type of side chain showed high binding affinities in range of K(i)= 3-5 nM and excellent antitumor profiles, particularly against the colo205 colon cancer and the K562 leukemia cell lines. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Entities: CellLine Chemical Disease Gene Species

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Year: 2009 PMID： 20045644 PMCID： PMC3725291 DOI： 10.1016/j.bmcl.2009.12.058

Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823

16 in total

Review 1. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.

Authors: A C Newton
Journal: Chem Rev Date: 2001-08 Impact factor: 60.622

Review 2. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.

Authors: Y Nishizuka
Journal: Science Date: 1992-10-23 Impact factor: 47.728

3. Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.

Authors: Dehui Duan; Dina M Sigano; James A Kelley; Christopher C Lai; Nancy E Lewin; Noemi Kedei; Megan L Peach; Jeewoo Lee; Thushara P Abeyweera; Susan A Rotenberg; Hee Kim; Young Ho Kim; Saïd El Kazzouli; Jae-Uk Chung; Howard A Young; Matthew R Young; Alyson Baker; Nancy H Colburn; Adriana Haimovitz-Friedman; Jean-Philip Truman; Damon A Parrish; Jeffrey R Deschamps; Nicholas A Perry; Robert J Surawski; Peter M Blumberg; Victor E Marquez
Journal: J Med Chem Date: 2008-08-13 Impact factor: 7.446

Review 4. Complexities of the protein kinase C pathway.

Authors: P M Blumberg
Journal: Mol Carcinog Date: 1991 Impact factor: 4.784

5. Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?

Authors: K Nacro; B Bienfait; J Lee; K C Han; J H Kang; S Benzaria; N E Lewin; D K Bhattacharyya; P M Blumberg; V E Marquez
Journal: J Med Chem Date: 2000-03-09 Impact factor: 7.446

6. Differential regulation by anti-tumor-promoting 12-deoxyphorbol-13-phenylacetate reveals distinct roles of the classical and novel protein kinase C isozymes in biological responses of primary mouse keratinocytes.

Authors: Z Szallasi; K Kosa; C B Smith; A A Dlugosz; E K Williams; S H Yuspa; P M Blumberg
Journal: Mol Pharmacol Date: 1995-02 Impact factor: 4.436

7. Nonpromoting 12-deoxyphorbol 13-esters inhibit phorbol 12-myristate 13-acetate induced tumor promotion in CD-1 mouse skin.

Authors: Z Szallasi; L Krsmanovic; P M Blumberg
Journal: Cancer Res Date: 1993-06-01 Impact factor: 12.701

Polar 3-alkylidene-5-pivaloyloxymethyl-5'-hydroxymethyl-gamma-lactones as protein kinase C ligands and antitumor agents.

Review 1. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.

Review 2. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.

3. Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities.

Review 4. Complexities of the protein kinase C pathway.

5. Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?

6. Differential regulation by anti-tumor-promoting 12-deoxyphorbol-13-phenylacetate reveals distinct roles of the classical and novel protein kinase C isozymes in biological responses of primary mouse keratinocytes.

7. Nonpromoting 12-deoxyphorbol 13-esters inhibit phorbol 12-myristate 13-acetate induced tumor promotion in CD-1 mouse skin.

Review 8. Bryostatin-1: a novel PKC inhibitor in clinical development.

Review 9. Regulation of protein kinase C and role in cancer biology.

Review 10. Synthetic diacylglycerols (DAG) and DAG-lactones as activators of protein kinase C (PK-C).

Review 1. Natural and Synthetic Lactones Possessing Antitumor Activities.