Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels-Alder Pattern Common to Three Classes of Natural Products.

Identification of a common Diels-Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from ß,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered ß,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.

S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth.

Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. Ex vivo, S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.

S38151 [p-guanidinobenzoyl-[Des-Gly(10)]-MCH(7-17)] is a potent and selective antagonist at the MCH(1) receptor and has anti-feeding properties in vivo.

Structure-activity relationships studies have established the minimal sequence of melanin-concentrating hormone (MCH) that retains full agonist potency at the MCH(1), to be the dodecapeptide MCH(6-17). The alpha-amino function is not required for activity since arginine(6) can be replaced by p-guanidinobenzoyl, further improving activity. We report that the deletion of glycine in this short potent agonist (EC(50) 3.4nM) turns it into a potent and new MCH(1) antagonist (S38151, K(B) 4.3nM in the [(35)S]-GTPgammaS binding assay), which is selective versus MCH(2). A compared Ala-scan of the agonist and antagonist sequences reveals major differences in the residues that are mandatory for affinity, including arginine(11) and tyrosine(13) for the agonist and leucine(9) for the antagonist, whereas methionine(8) was necessary for both agonist and antagonist activities. A complete molecular study of the antagonist behavior is described in the present report, with a particular focus on the description of several analogues, attempting to find structure-activity relationships. Finally, S38151 antagonizes food intake when injected intra-cerebroventricularly in the rat. This is in agreement with the in vitro data and with our previous demonstration of a good correlation between in vitro and in vivo data on MCH(1) agonists.