Oncogenes and Tumor Suppressors Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations

Abstract KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13D mutation as shown by Xray crystallography. High-resolution X-ray structures are also provided for the GDP-bound forms of KRAS G12V, G12R, and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRASdriven tumors that preferentially signal through RAF. Implications: Biochemical profiling and subclassification of KRAS-driven cancers will enable the rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors

A General Method for Synthesis of Isomaleimide Derivatives

A mild and efficient method for the synthesis of isoimide by a simple reaction of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) with various kinds of maleimicacid, succimicacid, pthaleimicacid in dichloromethane at room temperature is described

Synthesis of Chain Transfer Agents for RAFT Polymerization by using DBU

Trithiocarbonate TTC, Dithioester DT containing RAFT chain transfer acid agents are efficiently and conveniently esterified by DBU. The significance of the reaction is mild reaction condition, high yield, easy simple workup, and reduction of reaction time. This protocol providing a useful alternative method for ester synthesis and makes the process very viable or more economic

Reactivity Studies of Thiophosgene and its Halo Versions towards Diazo Derivatives

The reactions of thiophosgene with diazo derivatives gives dichloro-alkene derivatives and cyclized, 1,2,3-thiadiazoles respectively. The product formation is mainly depending on substitutions on diazo substrates. When its halo versions, CSBr2 and in combination with bromide ion, CSBr2 less reactive than bromide ion with disubstituted diazo, give gem-dihalo derivatives whereas more reactive with mono substituted diazo to gives 1,2,3-thiadiazoles. In case CSI2 irrespective of substitution on diazo, iodide ion is more reactive then CSI2 was observed

Synthetic Studies of Maleimide Derivatives for Bioconjugates Polymers by RAFT polymerization.

An efficient method for the synthesis of maleimides derivatives in toluene in presence of PTSA is described. The method features a broad substrate scope of utility in both simple and complex setting and provide access to valuable derivatives without any column chromatography purification is described

O-Mesityl(sulfonyl)hydroxylamine: A Novel Reagent for Reduction of Electron Deficient α,β-Unsaturated Carbonyl Derivatives

Hydrogenation of electron deficient ,-unsaturated carbonyl derivativesusing O-mesityl(sulfonyl)hydroxylamine in the presence of catalytic amount of ytterbiumtriflate to obtain good to excellent is described.</div

Synthesis of Ruthenium Bipyridyl Linked with Steroidal Oxidative Quencher for Photo Redox Studies

Abstract: Synthesis of ruthenium bipyridyl linked with steroid having oxidative quencher, viologens for study of photo redox properties were described.</p

Diastereoselective Cyclopropanation by Using Camphorpyrazolidinone Derived α,β-Unsaturated Amides and Ylide

Abstract: High to moderate diastereoselectivity and high chemical yield are observed in the Michael addition of ylide and chiral camphorpyrazolidinone ylide to an optically pure a,b-unsaturated carboxylic acid derivatives derived from a chiral camphorpyrazolidinone and a,b-unsaturated carbonyl respectively. A novel route to the asymmetric synthesis of cyclopropanation derivatives is described.</p

Green Synthesis: A Novel Method for Bromination of 7-AminoPhthalide

A novel method for preparing a bromo substituted 7-Amino-phthalides and 7-Amino-3-hydroxy-phthalides via the bromonium ion intermediate under acidic conditions athigher temperature were developed. The results will illustrate the potential utility of thismethod as an environment-friendly process for synthesis of bromo substituted aryl amines,along with conservation of half mole equivalent of halides.</div