ABSTRACT
An enantioselective arylation reaction catalyzed by palladium complexed with substituted phosphinooxazoline (PHOX) ligands is described. Aza-quaternary stereocenters are readily accessible through the arylation reaction between cyclic iminosulfates and a wide variety of arylboronic acids, including electron-poor and ortho-substituted arylboronic acids. This reaction was applied to the preparation of verubecestat, which is currently undergoing clinical evaluation for the treatment of Alzheimer's disease.
ABSTRACT
A rapid and efficient synthesis of a series of C2-symmetric 17beta-estradiol homo-dimers is described. The new molecules are linked at position 17alpha of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in only five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER+ and ER-) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER+ cell line. However, they are not very cytotoxic when compared to the antiestrogen tamoxifen. Unfortunately, they show only weak affinity for the estrogen receptor alpha (ERalpha) and no affinity for the estrogen receptor beta (ERbeta). The new compounds were also tested on human intestinal (HT-29) cancer and on murine skin cancer (B16-F10) cell lines for further biological assessment. Interestingly, the dimers were found to be cytotoxic to the murine skin cancer cell line but were inactive towards the intestinal cancer cell line.
Subject(s)
Estradiol/chemical synthesis , Estradiol/pharmacology , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Breast Neoplasms , Cell Line, Tumor , Dimerization , Estradiol/chemistry , Humans , Intestinal Neoplasms , Magnetic Resonance Spectroscopy , Protein Binding , Skin Neoplasms , Spectrophotometry, InfraredABSTRACT
A rapid and efficient synthesis of a series of C(2)-symmetric 17 beta-estradiol dimers is described. The new molecules are linked at position 17 alpha of the steroid nucleus with either an alkyl chain or a polyethylene glycol chain. They are made from estrone in five chemical steps with an overall yield exceeding 30%. The biological activity of these compounds was evaluated in vitro on estrogen dependent and independent (ER(+) and ER(-)) human breast tumor cell lines: MCF-7 and MDA-MB-231. Some of the dimers present selective cytotoxic activity against the ER(+) cell line.
Subject(s)
Estradiol/analogs & derivatives , Estradiol/chemical synthesis , Alkylation , Binding, Competitive/drug effects , Breast Neoplasms/metabolism , Colorimetry , Coloring Agents , Estradiol/pharmacology , Estrone/chemical synthesis , Estrone/pharmacology , Female , Humans , Polyethylene Glycols , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Microwave heating methods have been combined with the use of solid-supported catalysts to produce small solution-phase libraries of medicinally-relevant compounds. Palladium supported on charcoal (Pd/C) has been used to produce libraries of pyrazole compounds for screening in COX II studies via Suzuki cross coupling reactions, while the same catalyst has been used also to produce styryl-based nAChR compounds using analogous chemistry. Although the reaction substrates are very different (aryl vs. vinyl), this catalyst system provided consistently good and reliable results. The use of a polystyrene-supported Ru catalyst for ring-closing metathesis (RCM) reactions was also evaluated to prepare benzolactam structures for evaluation as factor Xa inhibitors.
