1380328-08-4Relevant academic research and scientific papers
New [apurishiatokishin[apurishiatokishin] derivative containing anticancer agents
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, (2017/09/08)
The invention provides an aplysiatoxin derivative represented by formula (I), or a pharmaceutically acceptable salt thereof, that is a PKC activator having no carcinogenesis-promoting activity that can serve as an alternative to Bryo-1 as a novel compound that can be used as an anticancer agent. (In formula (I), R1 is a hydrogen atom or hydroxyl group; R2 is a hydrogen atom or methyl group; R3 is a hydrogen atom or methyl group; R4 is a hydrogen atom or methyl group; R5 is a hydrogen atom or methyl group; and R6 is represented by a substituent selected from any of a hydrogen atom, halogen atom, acetylamino group, hydroxyl group, or optionally substituted alkyl group having 1-5 carbon atoms.)
Improved and large-scale synthesis of 10-methyl-aplog-1, a potential lead for an anticancer drug
Kikumori, Masayuki,Yanagita, Ryo C.,Irie, Kazuhiro
, p. 9776 - 9782 (2015/01/09)
10-Methyl-aplog-1 (1), a simplified analog of tumor-promoting aplysiatoxin, is a potential lead for cancer therapy that exhibits marked and selective growth inhibitory effects against several human cancer cell lines and negligible tumor-promoting activity in vivo. However, more detailed evaluations of its toxicity and anticancer activity in vivo are hampered by supply problems associated with a non-optimal synthetic method. We here addressed this issue through a more practical and reliable synthetic method that afforded several hundred milligrams of 1 with high purity (>98%) in 23 steps from commercially available m-hydroxycinnamic acid with an overall yield of 1.1%. The utilization of two key reactions, substrate-controlled epoxidation and the oxidative cleavage of alkene with a free hydroxyl group, successfully reduced the existing five synthetic steps and markedly improved the handling of large amounts of intermediates. We also demonstrated for the first time that such an analog was synthetically accessible in reliable quantities and also that this large supply could advance in vivo trials for the treatment of cancer.
Structure-activity studies on the spiroketal moiety of a simplified analogue of debromoaplysiatoxin with antiproliferative activity
Kikumori, Masayuki,Yanagita, Ryo C.,Tokuda, Harukuni,Suzuki, Nobutaka,Nagai, Hiroshi,Suenaga, Kiyotake,Irie, Kazuhiro
, p. 5614 - 5626 (2012/08/29)
Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar Ki values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.
