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An efficient systematic approach to the diversity-oriented synthesis of polyketides has been developed to provide both skeletal and stereochemical diversity. Each synthetic intermediate is also a desired polyketide fragment and no protecting group manipulations are required. A first-generation synthesis provides a 74-membered polyketide library comprising six different skeletal classes, each in one to five steps from propargylic alcohol precursors. A study of epoxyol opening reactions revealed unusual reactivity trends based on epoxide configuration.

Construction of the AB-ring system of the taxane framework via an A-ring annulation strategy was demonstrated by base-mediated intramolecular aldol reaction of (Z)-2,2-dimethyl-3-(1-methyl-2-oxopropylidene)cyclooctanone, affording the title compound, 1-hydroxy-8,11,11-trimethylbicyclo[5.3.1]undec-7-en-9-one. A cyclization precursor, the tetra-substituted (Z)-alkene, was prepared from the corresponding cyclooctanone derivative, 3-[(alpha,alpha- dimethylbenzyl)dimethylsiloxy]-2,2-dimethylcyclooctanone via a bicyclic alpha,beta-unsaturated lactone intermediate.

Asymmetric total syntheses of Taxol and of 8-demethyltaxoids 24-27 from the 8-membered ring compounds 29 and 12 respectively were completed via successive formation of the BC ring system by intramolecular aldol reaction, then the ABC ring system utilizing an intramolecular pinacol cyclization. The conversion of the tricyclic compound 43 to 7-TES baccatin III (49) was carried out by way of a newly devised method of constructing the oxetane ring. The dehydration condensation between a derivative of N- benzoylphenylisoserine and 49, followed by deprotection afforded the antitumor agent Taxol.

The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy. In particular, MEK is an attractive drug target due to its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK. We synthesized derivatives of N-[2-(2-Chloro-4-iodo-phenylamino)-3,4-difluorophenyl] -methanesulfonamide as novel MEK1/2 inhibitors. Among these compounds, we found SMK-17 to be a potent MEK1/2 inhibitor with high aqueous solubility. The in silico docking study suggested that SMK-17 be bound to an allosteric pocket of MEK1. The kinetics study and kinase profiler analysis confirmed the allosteric character of SMK-17. SMK-17 inhibited MEK1 kinase activity by a non-ATP-competitive manner and it was highly selective to MEK1 and 2. SMK-17 inhibited the growth of tumor cell lines in vitro. Especially, it seemed that cell lines harboring highly phosphorylated MEK1/2 and ERK1/2 were highly sensitive to SMK-17. Moreover, unlike previously reported MEK inhibitors, PD184352 or U0126, SMK-17 did not inhibit phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models by oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways, which resulted in significant antitumor efficacy without notable side effects. In conclusion, we found very potent MEK inhibitor SMK-17 from our structure-activity correlation study of new derivative series of diphenyl amine sulfonamide. Kinase profiler and kinetics study revealed that SMK-17 is a non-ATP-competitive and highly selective MEK1/2 inhibitor. Moreover, SMK-17 exhibited potent antitumor activity in animal models by oral administration. SMK-17 selectively blocked the MAPK pathway signaling without affecting other signal pathways both in vitro and in vivo. These findings suggest that SMK-17 is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling. Furthermore, we are now investigating the combination effects of SMK-17 with several drugs, and studying about prediction marker of this compound. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B133.