Synthesis of cyclic 2-enones from cyclic 1,3-diketones

Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents.

Abstract: A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (eg 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials

Design, synthesis, and evaluation of small molecule Hsp90 probes

Abstract: A number of compounds from different chemical classes are known to bind competitively to the ATP-pocket of Hsp90 and inhibit its chaperone function. The natural product geldanamycin was the first reported inhibitor of Hsp90 and since then synthetic inhibitors from purine, isoxazole and indazol-4-one chemical classes have been discovered and are currently or soon to be in clinical trials for the treatment of cancer. In spite of a similar binding mode to Hsp90, distinct biological profiles were demonstrated among these molecules, both in vitro and in vivo. To better understand the molecular basis for these dissimilarities, we report here the synthesis of chemical tools for three Hsp90 inhibitor classes. These agents will be useful for probing tumor-by-tumor the Hsp90 complexes isolated by specific inhibitors. Such information will lead to better understanding of tumor specific molecular markers to aid in their clinical development. It will also help to elucidate the molecular basis for the biological differences observed among Hsp90 inhibitors.

A regioselective and stereospecific synthesis of allylsilanes from secondary allylic alcohol derivatives

Abstract: Primary and secondary allylic acetates and benzoates react with the dimethyl (phenyl)silyl-cuprate reagent to give allylsilanes, provided that the THF in which the cuprate is prepared is diluted with ether before addition of the allylic ester. The reaction is reasonably regioselective in some cases: (i) when the allylic system is more-substituted at one end than the other, as in the reactions 4→5 and 9→10; (ii) when the steric hindrance at one end is neopentyl-like, as in the reactions 15→16; and (iii) when the disubstituted double bond has the Z configuration, as in the reactions Z-19→E-21 or, better, because the silyl group is becoming attached to the less-sterically hindered end of the allylic system, Z-20→E-22. The regioselectivity is better if a phenyl carbamate is used in place of the ester, and a three-step protocol assembling the mixed cuprate on the leaving group is used, as in the reactions 23→24 and E- or Z-29→E-21, or, best of all, because the silyl group is again becoming attached to the less-sterically hindered end of the allylic system, E- or Z-30→E-22. This sequence works well to move the silyl group onto the more substituted end of an allyl system, but only when the move is from a secondary allylic carbamate to a tertiary allylsilane, as in the reaction 38→39. Allyl(trimethyl)silanes can be made using alkyl- or aryl-cuprates on trimethylsilyl-containing allylic esters and carbamates, as in the reactions 40→41, and 43→44. The reaction of the silyl-cuprate with allylic esters and the three-step sequence with the allylic carbamates are stereo-chemically complementary, the former being stereospecifically anti and the latter stereospecifically syn. Homochiral allylsilanes can be made by these methods with high levels of stereospecificity, as shown by the synthesis of the allylsilanes 54, 58 and 59.

New oxidative demetalation protocol for molybdenum π-complexes: Enantiocontrolled synthesis of unsaturated ketones and lactones

Abstract: An efficient and general oxidative demetalation of (η3-allyl)molybdenum complexes using pyridinium dichromate allows the introduction of a carbonyl group at an allylic terminus of the π-system. The...

Chapter 1 Dimedone: A Versatile Precursor for Annulated Heterocycles

Abstract: Publisher Summary This chapter explores that dimedone is a versatile precursor for annulated heterocycles. Dimedone(1) is an alicyclic compound having 1,3-dicarbonyl groups flanked by a methylene group and exists in a tautomeric transenolized form where intramolecular hydrogen bonding is not possible. Dimedone is an excellent precursor for partially hydrogenated fused heterocycles where two of the carbon atoms of dimedone are part of the backbone of the formed heterocycles. The chapter illustrates that dimedone's structural features and its reactivity to form more functionalized derivatives have led to the construction of a wide range of fused or spiral biheterocycles. Finally, this chapter emphasizes the role of 1 in the synthesis of fused heterocycles, classified according to the size of the ring and the number of heteroatoms in the heterocycle fused to the cyclohexane ring and subdivided according to the heteroatoms and their arrangement in the ring.