Loss of the Phenolic Hydroxyl Group and Aromaticity from the Side Chain of Anti-Proliferative 10-Methyl-aplog-1, a Simplified Analog of Aplysiatoxin, Enhances Its Tumor-Promoting and Proinflammatory Activities

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2017 Apr 14

PMID 28406454

Authors

Yusuke Hanaki

Masayuki Kikumori

Harukuni Tokuda

Mutsumi Okamura

Shingo Dan

Naoko Adachi

Naoaki Saito

Ryo C Yanagita

Kazuhiro Irie

Affiliations

Soon will be listed here.

Abstract

Aplysiatoxin (ATX) is a protein kinase C (PKC) activator with potent tumor-promoting activity. In contrast, 10-methyl-aplog-1 (), a simplified analog of ATX, was anti-proliferative towards several cancer cell lines without significant tumor-promoting and proinflammatory activities. To determine the effects of the phenolic group on the biological activities of , we synthesized new derivatives (, ) that lack the phenolic hydroxyl group and/or the aromatic ring. Compound , like , showed potent anti-proliferative activity against several cancer cell lines, but little with respect to tumor-promoting and proinflammatory activities. In contrast, exhibited weaker growth inhibitory activity, and promoted inflammation and tumorigenesis. The binding affinity of for PKCδ, which is involved in growth inhibition and apoptosis, was several times lower than those of and , possibly due to the absence of the hydrogen bond and CH/π interaction between its side chain and either Met-239 or Pro-241 in the PKCδ-C1B domain. These results suggest that both the aromatic ring and phenolic hydroxyl group can suppress the proinflammatory and tumor-promoting activities of and, therefore, at least the aromatic ring in the side chain of is indispensable for developing anti-cancer leads with potent anti-proliferative activity and limited side effects. In accordance with the binding affinity, the concentration of necessary to induce PKCδ-GFP translocation to the plasma membrane and perinuclear regions in HEK293 cells was higher than that of and . However, the translocation profiles for PKCδ-GFP due to induction by - were similar.

References

Nakagawa M, Oliva J, Kothapalli D, Fournier A, Assoian R, Kazanietz M . Phorbol ester-induced G1 phase arrest selectively mediated by protein kinase Cdelta-dependent induction of p21. J Biol Chem. 2005; 280(40):33926-34. DOI: 10.1074/jbc.M505748200. View

Wang Q, FANG T, Fenick D, Garfield S, Bienfait B, Marquez V . The lipophilicity of phorbol esters as a critical factor in determining the pattern of translocation of protein kinase C delta fused to green fluorescent protein. J Biol Chem. 2000; 275(16):12136-46. DOI: 10.1074/jbc.275.16.12136. View

Wang Q, Bhattacharyya D, Garfield S, Nacro K, Marquez V, Blumberg P . Differential localization of protein kinase C delta by phorbol esters and related compounds using a fusion protein with green fluorescent protein. J Biol Chem. 1999; 274(52):37233-9. DOI: 10.1074/jbc.274.52.37233. View

Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D . New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990; 82(13):1107-12. DOI: 10.1093/jnci/82.13.1107. View

Yanagita R, Kamachi H, Kikumori M, Tokuda H, Suzuki N, Suenaga K . Effects of the methoxy group in the side chain of debromoaplysiatoxin on its tumor-promoting and anti-proliferative activities. Bioorg Med Chem Lett. 2013; 23(15):4319-23. DOI: 10.1016/j.bmcl.2013.05.096. View

Maegawa T, Akashi A, Yaguchi K, Iwasaki Y, Shigetsura M, Monguchi Y . Efficient and practical arene hydrogenation by heterogeneous catalysts under mild conditions. Chemistry. 2009; 15(28):6953-63. DOI: 10.1002/chem.200900361. View

Shindo M, Irie K, Nakahara A, Ohigashi H, Konishi H, Kikkawa U . Toward the identification of selective modulators of protein kinase C (PKC) isozymes: establishment of a binding assay for PKC isozymes using synthetic C1 peptide receptors and identification of the critical residues involved in the phorbol ester.... Bioorg Med Chem. 2001; 9(8):2073-81. DOI: 10.1016/s0968-0896(01)00100-6. View

Keck G, Poudel Y, Cummins T, Rudra A, Covel J . Total synthesis of bryostatin 1. J Am Chem Soc. 2010; 133(4):744-7. PMC: 3030632. DOI: 10.1021/ja110198y. View

Baird W, Boutwell R . Tumor-promoting activity of phorbol and four diesters of phorbol in mouse skin. Cancer Res. 1971; 31(8):1074-9. View

10.

Yamori T, Matsunaga A, Sato S, Yamazaki K, Komi A, Ishizu K . Potent antitumor activity of MS-247, a novel DNA minor groove binder, evaluated by an in vitro and in vivo human cancer cell line panel. Cancer Res. 1999; 59(16):4042-9. View

11.

Kamachi H, Tanaka K, Yanagita R, Murakami A, Murakami K, Tokuda H . Structure-activity studies on the side chain of a simplified analog of aplysiatoxin (aplog-1) with anti-proliferative activity. Bioorg Med Chem. 2013; 21(10):2695-702. DOI: 10.1016/j.bmc.2013.03.013. View

12.

Hui X, Reither G, Kaestner L, Lipp P . Targeted activation of conventional and novel protein kinases C through differential translocation patterns. Mol Cell Biol. 2014; 34(13):2370-81. PMC: 4054312. DOI: 10.1128/MCB.00040-14. View

13.

Kollar P, Rajchard J, Balounova Z, Pazourek J . Marine natural products: bryostatins in preclinical and clinical studies. Pharm Biol. 2013; 52(2):237-42. DOI: 10.3109/13880209.2013.804100. View

14.

Lu Y, Woo S, Krische M . Total synthesis of bryostatin 7 via C-C bond-forming hydrogenation. J Am Chem Soc. 2011; 133(35):13876-9. PMC: 3164899. DOI: 10.1021/ja205673e. View

15.

Trost B, Dong G . Total synthesis of bryostatin 16 using atom-economical and chemoselective approaches. Nature. 2008; 456(7221):485-8. PMC: 2728752. DOI: 10.1038/nature07543. View

16.

Ramos O, Masucci M, Klein E . Activation of cytotoxic activity of human blood lymphocytes by tumor-promoting compounds. Cancer Res. 1984; 44(5):1857-62. View

17.

Nakagawa Y, Kikumori M, Yanagita R, Murakami A, Tokuda H, Nagai H . Synthesis and biological evaluation of the 12,12-dimethyl derivative of Aplog-1, an anti-proliferative analog of tumor-promoting aplysiatoxin. Biosci Biotechnol Biochem. 2011; 75(6):1167-73. DOI: 10.1271/bbb.110130. View

18.

Serova M, Ghoul A, Benhadji K, Faivre S, Le Tourneau C, Cvitkovic E . Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther. 2008; 7(4):915-22. DOI: 10.1158/1535-7163.MCT-07-2060. View

19.

Kato Y, Scheuer P . Aplysiatoxin and debromoaplysiatoxin, constituents of the marine mollusk Stylocheilus longicauda (Quoy and Gaimard, 1824). J Am Chem Soc. 1974; 96(7):2245-6. DOI: 10.1021/ja00814a041. View

20.

Keck G, Poudel Y, Rudra A, Stephens J, Kedei N, Lewin N . Role of the C8 gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity. Bioorg Med Chem Lett. 2012; 22(12):4084-8. PMC: 3369313. DOI: 10.1016/j.bmcl.2012.04.073. View