The aryl hydrocarbon receptor (AhR) is a receptor/transcription factor which regulates cytochrome P450 (CYP) gene transcription and which is activated by environmental carcinogens, some of which are associated with increased breast cancer risk. Here, we show that the AhR is over-expressed and constitutively active in human and rodent mammary tumors, suggesting its ongoing contribution to tumorigenesis regardless of tumor etiology. AhR regulation of CYP1A1 and CYP1B1 was studied to determine if constitutively active AhR effects the same transcriptional outcomes as environmental chemical-activated AhR. Elevated AhR and CYP1B1 but not CYP1A1 before tumor formation in a rat model of mammary tumorigenesis suggested differential CYP1B1 regulation by a constitutively active AhR. This hypothesis was tested with human mammary gland cell lines which hyper-express AhR and CYP1B1 but which express little or no CYP1A1. CYP1B1 expression was diminished by repression of AhR activity or by AhR knockdown, demonstrating AhR control of basal CYP1B1 levels. ChIP assays demonstrated constitutive AhR binding to both CYP1A1 and CYP1B1 promoters, demonstrating that differential CYP1A1 and CYP1B1 regulation by constitutively active AhR does not result from different amounts of promoter-bound AhR. While increasing AhR binding to both CYP1A1 and CYP1B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin induced CYP1A1 mRNA in both a malignant and non-malignant line but increased only CYP1B1 mRNA in the malignant line, again demonstrating that the level of promoter binding does not necessarily correlate with gene mRNA levels. These studies suggest that constitutively active AhR mediates different molecular outcomes than environmental chemical-activated AhR, and further implicate the AhR in mammary tumorigenesis.

Alkyne hydrothiolation is a potentially attractive method for the formation of vinyl sulfides, which are valuable synthetic intermediates. Known methods for hydrothiolation using alkyl thiols are quite limited. We report herein that Tp*Rh(PPh3)2 (Tp* = hydrotris(3,5-dimethylpyrazolyl)borate) is a highly active catalyst for alkyne hydrothiolation with alkyl and aryl thiols. Hydrothiolation using alkyl thiols proceeds with excellent regioselectivity, providing convenient access to branched alkyl vinyl sulfides, which are difficult to synthesize by other means. A mixture of regioisomers is obtained when using aryl thiols, with the branched isomer as the major product, opposite that reported for other Rh complexes.

Described herein are the scope and limitations using Tp*Rh(PPh(3))(2) as a catalyst for alkyne hydrothiolation with alkyl thiols. In general, catalytic hydrothiolation proceeds in high yields and with high regioselectivity for a wide range of alkynes and thiols. A variety of functional groups were well-tolerated, including nitriles, amines, halogens, ethers, esters and silanes, although strongly coordinating groups were found to be incompatible with hydrothiolation. Both sterically encumbered alkynes and thiols were successful in hydrothiolation. Electron rich alkynes react more rapidly than electron deficient alkynes. Overall, this hydrothiolation protocol provides convenient access to a variety of functionalized branched alkyl vinyl sulfides.

A series of rhodium pyrazolylborate complexes [TpRRh(PPh3)2] {TpR = HBR‘3, R‘ = 3,5-dimethylpyrazolyl (1), pyrazolyl (3), 3-phenylpyrazolyl (4), or 3-phenyl-5-methylpyrazolyl (5)} and [BpRRh(PPh3)2] {BpR = H2BR‘2, R‘ = 3,5-dimethylpyrazolyl (2)} were prepared from [ClRh(PPh3)3] and KX (X = pyrazolylborate anion). Complexes 2−5 were characterized crystallographically. The solution structures of new complexes 4 and 5 were also examined by variable temperature NMR and IR spectroscopy. The catalytic activity of complexes 1−5 in alkyne hydrothiolation was then examined. It was found that disubstituted tris(pyrazolyl)borate complexes (1 and 5) give the best selectivity and yield in alkyne hydrothiolation with aliphatic thiols.

Thioethers Q 0580Rhodium-Catalyzed Alkyne Hydrothiolation with Aromatic and Aliphatic Thiols.-Hydro(trispyrazolyl)borate rhodium complex Tp x Rh(PPh3)2 is highly active for the alkyne hydrothiolation. The reaction with alkyl thiols proceeds with excellent regioselectivity and affords branched vinyl sulfides which are difficult to prepare by other means. Mixtures of regioisomers are formed in the case of aryl thiols with branched isomers as major products. -(CAO, C.; FRASER, L. R.; LOVE*, J. A.; J. Am. Chem. Soc. 127 (2005) 50, 17614-17615; Dep. Chem., Univ. British Columbia, Vancouver, B. C. V6T 1Z1, Can.; Eng.) -Klein 16-093