4 research outputs found
Asymmetric biomimetic oxidations of phenols: the mechanism of the diastereo- and enantioselective synthesis of dehydrodiconiferyl ferulate (DDP) and dehydrodiconiferyl alcohol (DDA)
No full textStereoselective bimolecular radical coupling of enantiopure phenylpropenoidic phenols are described, starting from enantiopure amidic derivatives of ferulic acid. The latter were prepared from ferulic acid by reaction with (S)-alanine or Oppolzer camphor sultam. The oxidation step was performed both enzymatically (HRP/H2O2) and chemically (Ag2O). The observed enantioselectivity in the oxidation step encompasses the range 65-84% and is consistent with the conformational analysis of the quinone methide intermediates at the PM3 level. (C) 2000 Elsevier Science Ltd. All rights reserved
ChemInform Abstract: The Formation of Dibenzodioxocin Structures by Oxidative Coupling. A Model Reaction for Lignin Biosynthesis.
No full textODM-208, a novel CYP11A1-inhibitor as a therapeutic approach for the treatment of castration-resistant prostate cancer
No full textCYP11A1 inhibition as a therapeutic approach for the treatment of castration resistant prostate cancer.
No full text 340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC. </jats:p
