High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design.

Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value.

Structure of human glycolate oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1,2,3-thiadiazole.

Glycolate oxidase, a peroxisomal flavoenzyme, generates glyoxylate at the expense of oxygen. When the normal metabolism of glyoxylate is impaired by the mutations that are responsible for the genetic diseases hyperoxaluria types 1 and 2, glyoxylate yields oxalate, which forms insoluble calcium deposits, particularly in the kidneys. Glycolate oxidase could thus be an interesting therapeutic target.

Synthesis and biological evaluation of vinca alkaloids and phomopsin hybrids.

Ten hybrids of vinca alkaloids and phomopsin A have been synthesized by linking the octahydrophomopsin lateral chain to the tertiary amine of the cleavamine moiety of anhydrovinblastine (AVLB) and vinorelbine. These compounds have been elaborated in order to obtain original products that may interfere with both binding sites of vinblastine (VLB) and phomopsin in tubulin. Although NMR and molecular modeling studies have shown that the orientation of the added peptide chains of these hybrids is not the same as those of phomopsin A, most of them are very potent inhibitors of microtubules assembly and they present good cytotoxicity against KB cell line.

New potent acetylcholinesterase inhibitors in the tetracyclic triterpene series.

A new highly selective inhibitor of acetylcholinesterase (AChE) was discovered by high-throughput screening. Compound 1 was synthesized from a natural product, the N-3-isobutyrylcycloxobuxidine-F 2. A new extraction protocol of this compound is described.

Novel C2-C3' N-peptide linked macrocyclic taxoids. Part 2: synthesis and biological activities of docetaxel analogues with a peptide side chain at C2 and their macrocyclic derivatives.

The synthesis of a series of novel docetaxel analogues possessing a peptide side chain at the C2 position as well as peptide macrocyclic taxoids is described. These compounds were designed to mimic a region of the alpha-tubulin loop equivalent to the paclitaxel binding pocket of beta-tubulin. Fifteen new peptide taxoids were obtained and evaluated as inhibitors of microtubule disassembly as well as cell proliferation.