Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.

In this paper, we will demonstrate the value of olefin cross metathesis as an effective synthetic tool for applications in the agrochemical and pharmaceutical industries. First, we will demonstrate the usefulness of cross metathesis reactions in the efficient synthesis of the major component of the Peach Twig Borer pheromone and the of Omnivorous Leafroller pheromone, insect pheromones are environmentally friendly pest‐controlling agents. Second, we will demonstrate highly efficient cross metathesis routes into novel α,β‐unsaturated carbonyl intermediates. These novel α,β‐unsaturated carbonyl intermediates can be further functionalized into pharmaceutical compounds that are difficult to prepare by the traditional synthetic methodologies. This paper highlights key catalyst‐substrate reactivity variations with different ruthenium olefin metathesis catalysts, highlights cross metathesis reactions and techniques and highlights an efficient ruthenium catalyst removal technique.

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

A formal, enantioselective synthesis of the antitumor antibiotic (+)−FR900482 (1) has been completed using an approach that featured the ring-closing metathesis of the diene 37 to give the key intermediate benzazocine 38. Although several initial protecting-group strategies unexpectedly failed at various stages of the endeavor, the successful approach to 1 involved the conversion of commercially available 5-nitrovanillin (10) into the prochiral diol 24. The manipulations of the residues on the aromatic ring of 10 were straightforward, and the diol array in 24 was introduced by the hydride reduction of the malonate 23, which was in turn prepared by a nucleophilic substitution of the triflate 12. Adjustment of alcohol-protecting groups to give 27 and refunctionalization of the aromatic nitro group led to the protected N-allylamine 36. Elaboration of the diol array via a highly stereoselective Grignard addition furnished the diene 37. Ring-closing metathesis of 37 using the Grubbs catalyst 34 cleanly afforded the benzazocine 38. A tactic originally conceived for preparing 42 by introduction of the aziridine ring onto 38 was impractical because the iodo cyclization of the allylic tosylcarbamate 39 was neither efficient nor selective to give 40. Hence, 38 was transformed into 49, which was a key intermediate in Fukuyama's elegant synthesis of racemic FR900482, thereby completing a formal synthesis of the alkaloid. The prochiral diol 24 was enzymatically desymmetrized using Pseudomonas species lipase to give 25 in 94% enantiomeric excess. Inasmuch as subsequent adjustment of the alcohol-protecting groups gave the intermediate 26 (cf the racemic analogue 27) in enantiomerically pure form, an enantioselective synthesis of (+)−FR900482 has also been completed in a formal sense.

Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O 5 -methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (F)-(2VR,3VR) having the naturally occurring enantiomer (2VR,3VR) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O 5 -methyl psorospermin, the order of biological potency is (2VR,3VR) > (2VR,3VS) = (2VS,3VR) > (2VS,3VS). This order of potency is also found in the topoisomerase IIinduced alkylation of O 5 -methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II -induced alkylation of DNA and the biological activity by psorospermin and its O 5 -methyl derivatives. Finally, (2VR,3VR) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2VR,3VR) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.