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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 because of its high selectivity to ERK. We can expect potent growth inhibitory and proapoptotic effects by inhibiting MEK. Here, we report 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 is bound to an allosteric pocket of MEK1. The kinetic study and the kinase profiler analysis confirmed the allosteric nature of SMK-17. SMK-17 inhibited MEK1 kinase activity in 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 the phosphorylation of ERK5. In vivo, SMK-17 exhibited potent antitumor activity in animal models on 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. These findings suggest that SMK-17, an exquisitely selective, orally available MEK1/2 inhibitor, is a useful chemical biology tool for characterizing the function of MEK/MAPK signaling both in vitro and in vivo.

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.

A new method for the total asymmetric synthesis of antitumor agent Taxol is described. Baccatin III, a complex carbon framework, is synthesized by way of B to BC to ABC ring construction. Further, a method of forming Taxol from baccatin III and a β-amino acid is also demonstrated.

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.

1-t-Butyldimethylsiloxy-8,11,11-trimethylbicyclo[5.3.1]undec-7-en-9-one (2) has been synthesized via intramolecular aldol condensation of the precursor 3 by combined use of lithium diisopropylamide (LDA) and CeCl3. The dicarbonyl compound 3 was prepared by allylation of 8-membered ring ketone 6b.

Optically active 9-t-butyldiphenylsiloxy-11,11-dimethyl-5-methoxymethoxy-1,2,6-tribenzyloxybicyclo[5.3.1]undec-3,7-diene (12) was synthesized from diketone 9 via an intramolecular aldol reaction. The diketone 9 was synthesized from 7-t-butyldimethylsiloxy-4,8-dibenzyloxy-6,6-dimethyl-5-p-methoxy-benzyloxy-2-cycloocten-1-one (1) by way of a two-step sequence using diastereoselective allylation with allylmagnesium bromide followed by Wacker oxidation.

Optically active 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(4-methoxybenzyloxy)–8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one 2 that corresponds to BC ring system of Taxol was prepared from 8-membered ring enone 3 in high yield via stereoselctive Michael addition and successive intramolecular aldol cyclization. The above 8-membered ring enone 3 was synthesized from the linear optically active polyoxy-compound 4 by SmI2-mediated intramolecular aldol cyclization.

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.

Baccatin III was efficiently synthesized from the BC ring system of Taxol,2α,10β-dibenzyloxy-11β-(t-butyldimethylsil-oxy)-7β-hydroxy-1α-(4-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bic...

Optically active novel 18-demethyltaxiods were successfully synthesized from 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(p-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one (2) which corresponds to the BC ring system of Taxol by stereoselective allylation and intramolecular aldol condensation reactions.

Optically active novel 18-demethyltaxiods were successfully synthesized from 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(p-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one (2) which corresponds to the BC ring system of Taxol by stereoselective allylation and intramolecular aldol condensation reactions.

Baccatin III was efficiently synthesized from the BC ring system of Taxol,2α,10β-dibenzyloxy-11β-(t-butyldimethylsil-oxy)-7β-hydroxy-1α-(4-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans-bic...

Optically active 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy-1α-(4-methoxybenzyloxy)–8β,15,15-trimethyl-4-methylene-trans-bicyclo[6.4.0]dodecan-9-one 2 that corresponds to BC ring system of Taxol was prepared from 8-membered ring enone 3 in high yield via stereoselctive Michael addition and successive intramolecular aldol cyclization. The above 8-membered ring enone 3 was synthesized from the linear optically active polyoxy-compound 4 by SmI2-mediated intramolecular aldol cyclization.

Optically active 1α-allyl-1β,11β-benzylidenedioxy-2α,10β-bis(benzyloxy)-7β,9β-isopropylidenedioxy-8α,12,12-trimethyl-4-methylenebicyclo[6.4.0]dodecane (2)1 which corresponds to BC ring system of 8-epitaxoids was prepared in high yield form ketoaldehyde 8 via intramolecular aldol cyclization and succesive stereoselective methylation reactions. The ketoaldehyde 8 was synthesized from 8-membered ring compound 3 by stereoselective Michael addition using higher-order cuprate.

Optically active 9-t-butyldiphenylsiloxy-11,11-dimethyl-5-methoxymethoxy-1,2,6-tribenzyloxybicyclo[5.3.1]undec-3,7-diene (12) was synthesized from diketone 9 via an intramolecular aldol reaction. The diketone 9 was synthesized from 7-t-butyldimethylsiloxy-4,8-dibenzyloxy-6,6-dimethyl-5-p-methoxy-benzyloxy-2-cycloocten-1-one (1) by way of a two-step sequence using diastereoselective allylation with allylmagnesium bromide followed by Wacker oxidation.

1-t-Butyldimethylsiloxy-8,11,11-trimethylbicyclo[5.3.1]undec-7-en-9-one (2) has been synthesized via intramolecular aldol condensation of the precursor 3 by combined use of lithium diisopropylamide (LDA) and CeCl3. The dicarbonyl compound 3 was prepared by allylation of 8-membered ring ketone 6b.