Selective and predicable amine conjugation sites by kinetic characterization under excess reagents.

The site selectivity for lysine conjugation on a native protein is difficult to control and characterize. Here, we applied mass spectrometry to examine the conjugation kinetics of Trastuzumab-IgG (Her-IgG) and α-lactalbumin under excess linker concentration ([L]) based on the modified Michaelis-Menten equation, in which the initial rate constant per amine (k = V/K) was determined by the maximum reaction rate (V) under saturated accessible sites and initial amine-linker affinity (1/K). Reductive amination (RA) displayed 3-4 times greater V and a different panel of conjugation sites than that observed for N-hydroxysuccinimide ester (NHS) chemistry using the same length of polyethylene glycol (PEG) linkers.

Copper(I)-Catalyzed Nitrile-Addition/-Arylation Ring-Closure Cascade: Synthesis of 5,11-Dihydro-6-indolo[3,2-]quinolin-6-ones as Potent Topoisomerase-I Inhibitors.

In this paper, we present a copper(I)-catalyzed nitrile-addition/-arylation ring-closure cascade for the synthesis of 5,11-dihydro-6-indolo[3,2-]quinolin-6-ones from 2-(2-bromophenyl)--(2-cyanophenyl)acetamides. Using CuBr and -BuONa in dimethylformamide (DMF) as the optimal reaction conditions, the cascade reaction gave the target products, in high yields, with a good substrate scope. Application of the cascade reaction was demonstrated on the concise total syntheses of alkaloid isocryptolepine.

Synthesis and antiproliferative activities of ottelione a analogues.

Through the syntheses of its C-1 desvinyl, C-7 methylene, C-7 exocyclic ethylidene, and various C-3 phenylmethyl analogues, the structure-activity relationship of antimitotic ottelione A (4) against tubulin and various cancer cells was established. The results indicated that compound 4 was a colchicine-competitive inhibitor and that the C-1 vinyl group is unnecessary for its potency, whereas the C-7 exocyclic double bond is essential, possibly because of its irreversible interaction with tubulin. Further optimization of the substituents on the phenylmethyl group at the C-3 position generated compound 10g with a 3'-fluoro-4'-methoxyphenylmethyl substituent, which was 6-38-fold more active against MCF-7, NCI-H460, and COLO205 cancer cells relative to 4.

Synthesis and structure-activity relationship of 3-O-acylated (-)-epigallocatechins as 5α-reductase inhibitors.

A series of 3-O-acylated (-)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (-)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products.

Discovery of pyrrole-indoline-2-ones as Aurora kinase inhibitors with a different inhibition profile.

A series of pyrrole-indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3' position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50=2.

Synthesis of selenophene derivatives as novel CHK1 inhibitors.

A series of selenophene derivatives 3 were synthesized as potential CHK1 inhibitors. The effects of substitution on the 4'- or 5'-position of selenophene moiety and shifting the hydroxyl group position on C6- phenolic ring of oxindole were explored. This study led to the discovery of the most potent CHK1 inhibitors 29-33 and 39-43, which had IC(50) values in the subnanomolar range.