Graham B. Jones

Prospective, Multicenter, Randomized Phase II Trial of the Herbal Supplement, PC-SPES, and Diethylstilbestrol in Patients With Androgen-Independent Prostate Cancer

PURPOSE To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC). PATIENTS AND METHODS A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES. RESULTS Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines > or = 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots. CONCLUSION PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.

Catalytic asymmetric induction Part 2. Chiral tricarbonyl (η6 arene) chromium (0) complexes as enantioselective catalysts

Abstract A chiral metallocyclic Lewis acid based catalyst system derived from norephedrine is reported. A key stereodirective element emanates from a tricarbonyl chromium (0) group complexed to the aryl ring. The catalysts mediate the addition of dialkyl zinc species to a variety of aldehydes with high enantioselectivity.

Protein degradation with photoactivated enediyne-amino acid conjugates.

A series of photoactivated enediynes was prepared, and successfully employed for the selective degradation of target proteins.

On the origins of enantioselectivity in oxazaborolidine mediated carbonyl reductions

Abstract A series of tricyclic oxazaborolidine catalysts have been prepared from readily available ( S )-indoline-2-carboxylic acid. In each case, an arene chromium(0) carbonyl group was introduced on one face of the catalyst. Results obtained in the borane mediated reduction of ketones highlight the stereodirective importance of the α,α-appendages in the catalyst architecture.

A mild and efficient route to the pharmacophore of the enediyne antitumor agents : (Z)-1,6-[bis (trimethylsilyl)]-hex-3-ene-1,5-diyne via a novel carbenoid coupling reaction

(Z)-1,6-[Bis (trimethylsilyl)]-hex-3-ene-1,5-diyne has been prepared in high yield and in one pot from trimethylsilylpropargyl bromide by a remarkably stereoselective tandem carbenoid coupling-HX elimination sequence.

Photoactivated enediynes as targeted antitumoral agents: Efficient routes to antibody and gold nanoparticle conjugates

Efficient syntheses of a series of functionalized aryl enediynes have been developed. The building blocks were used to effect conjugation to carrier PEG templates which allowed subsequent coupling to a cardiac targeted monoclonal antibody. Immunocompetence of the enediyne-Mab conjugates was demonstrated by ELISA, and both parent enediynes and bioconjugates underwent successful photo-Bergman cyclization. Finally, surface modified (Au) nanoparticle conjugates were prepared and size confirmed by TEM analysis. Application as long-circulating photoactivated prodrugs is anticipated.

An intramolecular arylation route to the kinafluorenones

Intramolecular palladium-mediated arylation approaches to benzo[b]fluorenes have been investigated. The methodology has been applied in a short synthesis of kinafluorenone 2, providing an effective alternative to Friedel–Crafts-based approaches.

Chiral arene chromium tricarbonyl complexes as enantioselective catalysts: highly selective 1,2 alkyl additions to aldehydes

Abstract The preparation of a rationally designed catalyst system derived from norephedrine is reported. The key stereodirective element emanates from a chromium tricarbonyl group complexed to one face of the aryl ring. The catalysts mediate the addition of diethyl zinc to a variety of aldehydes with extremely high enantioselectivity.

Enantioselective route to α-hydroxy aldehyde and acid derivatives

Abstract Methodology is described for the enantioselective synthesis of chiral O-protected α-hydroxy aldehydes, acids and esters from achiral aldehydes having one less carbon.

Bidentate planar chiral η6-arene tricarbonyl chromium(0) complexes: ligands for catalytic asymmetric alkene hydrosilylation

Abstract S E Ar-type reactions of various heterocycles with ortho -substituted (1′ S , P )-tricarbonyl[(1-chloroethyl)-η 6 -benzene]chromium(0) derivatives lead to a family of novel planar chiral bidentate and pseudo-bidentate ligands. Two members of this family (1′ S , P )-2-[1′-tricarbonyl-η 6 -((2″- P , P -diphenylphosphino)phenyl)-chromium(0))ethyl] furan and thiophene show high activity and enantioselectivity in the Pd-catalyzed hydrosilylation of styrenes.