Chemical, conformational and structure-activity studies of taxol and related taxanes are detailed. Semisynthetic methodology for the preparation of taxol and related analogues with modified C-l3 phenylisoserine side chains was developed and analogues, modified at the C-3' phenyl group and the N-benzoyl group, were prepared. 3'-Cyclohexyl and 2-cyclohexylcarbonyl taxol analogues and C-13 side chain homologated derivatives were synthesized. Methods for the selective hydrolysis of all ester groups in baccatin ΙΠ and the conversion of 4-deacetylbaccatin III to 4-deacetyltaxol are reported. Reduction of taxanes with samarium diiodide provided 10-deacetyl derivatives as well as 9-dihydrotaxanes. Conformational analysis of taxol and other bioactive derivatives demonstrated the formation of hydrophobically clustered conformations in aqueous solvents.The discovery by the Potier group that 10-deacetylbaccatin III (4) can be isolated in significant quantities from a regenerable source, the needles of the European yew tree Taxus baccata L., was the most significant finding in the attempt to secure the long term supply of the anticancer agent taxol (1) through semisynthesis (Fig. 1) (7). Extraction of the fresh needles yields 4 in amounts of up to lg/kg, which is about ten times the amount of taxol isolated from the bark (0. lg/kg). It is of importance to note that the needles are a fully regenerable source and that their harvest does not threaten the survival of the yew species. The availability of 4 also facilitated semisynthetic studies directed at the elucidation of the taxol pharmacophore (2,3). Synthesis and Biological Evaluation of C-13 Chain Modified Taxol AnaloguesSince the C-13 Af-benzoyl-3-phenylisoserine side chain of taxol is of crucial importance for taxol's cytotoxicity (4), efficient methodology for the asymmetric synthesis of the C-13 side chain 2 and its attachment to baccatin III required development (5). NOTE: Paclitaxel is the generic name for Taxol, which is now a registered trademark. 0097-6156/95/0583-0217$08.00/0

Methionine aminopeptidase-2 (MetAP2) is an enzyme that cleaves an N-terminal methionine residue from a number of newly synthesized proteins. This step is required before they will fold or function correctly. Pre-clinical and clinical studies with a MetAP2 inhibitor suggest that they could be used as a novel treatment for obesity. Herein we describe the discovery of a series of pyrazolo[4,3-b]indoles as reversible MetAP2 inhibitors. A fragment-based drug discovery (FBDD) approach was used, beginning with the screening of fragment libraries to generate hits with high ligand-efficiency (LE). An indazole core was selected for further elaboration, guided by structural information. SAR from the indazole series led to the design of a pyrazolo[4,3-b]indole core and accelerated knowledge-based fragment growth resulted in potent and efficient MetAP2 inhibitors, which have shown robust and sustainable body weight loss in DIO mice when dosed orally.

Taxol (1) is a highly potent antitumor agent, exerting its mechanism of action by promoting the assembly of stable microtubules in cells. We are reporting on the first synthesis and biological evaluation of taxol derivatives with substituted phenyl rings at the C-13 N-benzoyl-(2'R,3'S)-3'-phenylisoserine side chain of taxol (1). Two taxol derivatives were synthesized, one possessing a N-(p-chlorobenzoyl)-(2'R,3'S)-3'-phenylisoserine side chain (2) and the other one a N-benzoyl-(2'R,3'S)-3'-(p-chlorophenyl)isoserine side chain (3). The synthesis of the novel phenylisoserine side chains was achieved through the asymmetric synthesis of 3-hydroxy-4-aryl-2-azetidinone derivatives via the ester enolate-imine cyclocondensation reaction. The 2-azetidinones 14 and 15 were acylated with p-chlorobenzoyl chloride and benzoyl chloride, respectively, to form the N-acyl beta-lactams 16 and 17. Subsequent coupling of 16 and 17 to 7-(triethylsilyl)baccatin III (6) in the presence of pyridine and DMAP afforded, after removal of the protecting groups, the desired taxol analogues 2 and 3 in excellent yields. The newly synthesized derivatives 2 and 3 were tested in the tubulin assembly assay and also evaluated for their cytotoxicity against B16 melanoma cells. It was found that the taxol derivatives 2 and 3 had activity comparable to taxol (1).

Apoptosis signal-regulating kinase 1 (ASK1/ MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury. KEYWORDS:Apoptosis signal-regulating kinase 1 (ASK1), structure-based drug design (SBDD), cardiac injury A poptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase kinase kinase (MAP3K) family member residing upstream of both Jun N-terminal kinase (JNK) and p38. ASK1 is capable of activating JNK and P38 via the phosphorylation of intermediate kinases. ASK1 plays a role in the mammalian cell stress response and the induction of apoptotic cell death. It also contributes to a range of systemic diseases including heart failure 1 and acute ischemia/reperfusion injury, by reducing structural and functional integrity of the mitochondria in cardiac cells. 2−4 ASK1-deficient mice display reduced levels of cardiomyocyte apoptosis, hypertrophy, and interstitial fibrosis. 5 Thus, selective inhibition of ASK1 represents an attractive strategy for slowing or potentially reversing harmful tissue changes associated with various forms of heart failure.Using ASK1 structural information and deconstruction of known ASK1 inhibitors such as 1 and 2 (Figure 1), our research team generated a novel, potent, and orally bioavailable ASK1 inhibitor with favorable physicochemical properties to help further elucidate the role of ASK1 in cardiac injury. Compound 1 was an early lead for Takeda's ASK1 inhibitor program. 6 Compound 2 (GS-4997, Gilead Sciences) is a clinical stage ASK1 inhibitor, which has been evaluated as an experimental treatment for diabetic nephropathy and kidney fibrosis. 7 Key structural features with respect to ligand interactions within the ATP binding site were identified using our internal database as well as public domain crystal structures of small molecules in ASK1 and published pharmacophore models. 8,9 Figure 1 illustrates the cocrystal structure of 1 in hASK1 (PDB: 3VW6) and highlights the key interactions between 1 and the ASK1 ATP binding pocket. Binding to the kinase hinge is characterized by a hydrogen bonding interaction with the

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