WYE-120318, a ring contraction product of methylnaltrexone, and structure revision of coniothyrione.

A contracted ring degradation product, WYE-120318 (compound 2), was discovered during the development phase for methylnaltrexone bromide (compound 1) drug substance. The compound was isolated by high-performance liquid chromatography fractionation, and its structure was determined by spectroscopic data analyses. WYE-120318 is formed from methylnaltrexone through a benzyl-benzilic acid type rearrangement reaction to yield an α-hydroxy-cyclopentanecarboxylic acid substructure. The proposed structure and the formation mechanism are confirmed by the synthesis of WYE-120318 from methylnaltrexone (compound 1). A similar benzyl-benzilic acid type rearrangement reaction can be envisioned as the biological origin of remisporine A (compound 3), a naturally occurring cyclopentadienyl compound that autocatalytically dimerizes to remisporine B (compound 4). The structure of remisporine A was deduced from its dimer 4. Coniothyione (compound 5) can be considered as the first example of a stable natural product bearing the remisporine A skeleton. However, the regiochemistry of the chlorosubstitution in the coniothyrione structure needs to be revised to compound 6 on the basis of the nuclear magnetic resonance data and biogenesis analysis.

Structural characterization of the tobramycin-piperacillin reaction product formed at pH 6.0.

Tobramycin is an aminoglycoside antibiotic that loses a significant amount of activity in the presence of Zosyn at pH 6. As part of our investigation into ways to improve the compatibility of tobramycin with Zosyn (which contains piperacillin and tazobactam in an 8:1 ratio buffered at pH 6 by sodium citrate) by lowering the pH, we identified the reaction product of tobramycin and piperacillin at pH 6.0 and the order of the pK(a) values of tobramycin. The structure of the main reaction product of tobramycin and piperacillin at pH 6.0 was determined by 2D NMR to be the product of 3″-NH(2) reacting with the ß-lactam of piperacillin. The order of the pK(a) values of the nitrogens of tobramycin was determined by (1)H and (15)N NMR titrations to be 6'-NH(2)>2'-NH(2)>1-NH(2)≈3″-NH(2)>3-NH(2). At pH 4.0, the reaction between tobramycin and Zosyn was almost negligible for a period of up to 2 h. The pH can be lowered by adding an acid such as HCl or citric acid to Zosyn to make a pH 4.0 buffer.

Isolation and structure of homotemsirolimuses A, B, and C.

Homotemsirolimuses A, B, and C (2a, 2b, 2c) were found to be minor components of a temsirolimus preparation made from rapamycin. These three temsirolimus analogues are derived from the corresponding rapamycin analogues, homorapamycins A, B, and C (1a, 1b, 1c) produced by the strain Streptomyces hygroscopicus. The structures of homotemsirolimuses A, B, and C were determined by spectroscopic methods. These compounds were tested for mTOR kinase inhibition and in two proliferation assays using LNCap prostate and MDA468 breast cancer cells. The results suggested that the mTOR inhibition and antiproliferation potencies for 2a, 2b, and 2c are comparable to those of rapamycin (1) and temsirolimus (2).

Complete assignments of the 1H and 13C resonances of 40-epi-(N1-tetrazolyl)-rapamycin and revised 13C assignments for rapamycin.

Complete 1H and 13C assignments of 40-epi-(N1-tetrazolyl)-rapamycin (ABT-578) in DMSO-d6 were made using 1H, 13C, DQCOSY, ROESY, TOCSY, HSQC and HMBC spectra. Comparing the assignments with those of rapamycin showed that in the published 13C assignments of rapamycin in DMSO-d6 the shifts for C-12 and C-42 have been interchanged, as well as the shifts for C-1 and C-8.

D-amino acid homopiperazine amides: discovery of A-320436, a potent and selective non-imidazole histamine H(3)-receptor antagonist.

Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.