Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors.

Proviral integration of Moloney virus 2 (PIM2) is a pro­survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan­PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The pan­PIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentration­dependent manner in multiple types of cancers; a similar result was observed with siRNA­mediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another pan­PIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasome­dependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.

Vicinal tricarbonyls and cyano analogs as electrophilic participants in forming pharmacophoric templates for drug discovery.

During recent years, fresh attention has been given to a functional group aggregate in which three carbonyl groups have been assembled in a 1,2,3-vicinal relationship. This vicinal tricarbonyl system represents a potent electrophilic unit, usually stabilized in the form of a monohydrate, which, in solution, is in equilibrium with the parent tricarbonyl. It reacts with a range of nucleophiles to form products that are not readily accessible via conventional routes. When an ancillary electrophilic functional group is appended to the vicinal tricarbonyl unit the resulting aggregate serves as a novel di- or trielectrophile in reaction with nucleophiles. This behavior is illustrated by the reaction of vicinal tricarbonyls, attached to vinyl and acetylenic groups, with a broad range of donor reagents to form key components of structures having biological relevance. Substitution of a cyano group for one of the terminal carbonyls leads to labile alpha, beta-diketo nitriles, which can be used as intermediates in forming alpha-ketoamide libraries of timely interest as protease inhibitors.

Indoloprodigiosins from the C-10 bipyrrolic precursor: new antiproliferative prodigiosin analogs.

The condensation of the C-10 methoxybipyrrole precursor (3) of prodigiosin with indoles and a related pyrrole derivative yields novel analogs of prodigiosin. Biological evaluation of these products revealed compounds that inhibit cancer cell proliferation from 50 nM to 50 microM.

Microwave-assisted concise total syntheses of quinazolinobenzodiazepine alkaloids.

[reactions: see text] One-pot total syntheses of the quinazolinobenzodiazepine alkaloids sclerotigenin (1), (+/-)-circumdatin F (2), and (+/-)-asperlicin C (3) via novel microwave-assisted domino reactions were achieved in 55%, 32%, and 20% yields, respectively, from commercially available starting materials. A two-step total synthesis of (+/-)-benzomalvin A (4) was accomplished with an overall yield of 16%. Additionally, analogues of circumdatin E were synthesized via the three-component one-pot sequential reactions promoted by microwave irradiation. Finally, a two-step formal total synthesis of (+/-)-asperlicin E (5) was also realized by using this microwave-assisted protocol.

Three-component one-pot total syntheses of glyantrypine, fumiquinazoline F, and fiscalin B promoted by microwave irradiation.

A microwave-promoted three-component one-pot reaction has been developed to provide access to the core pyrazino[2,1-b]quinazoline-3,6-dione (1) scaffold, which is common to several families of alkaloids with significant biological activities. By adapting this synthetic strategy through the use of selected Boc-amino acids and amino acid esters, we have accomplished highly efficient and concise total syntheses of glyantrypine (2), fumiquinazoline F (3), and fiscalin B (5), achieving overall yields of 55, 39, and 20%, respectively.

Novel one-pot total syntheses of deoxyvasicinone, mackinazolinone, isaindigotone, and their derivatives promoted by microwave irradiation.

[reaction: see text]. Total syntheses of deoxyvasicinone (1), mackinazolinone (2), and 8-hydroxydeoxyvasicinone (3) via novel microwave-assisted domino reactions, as well as a novel three-component one-pot total synthesis of isaindigotone (5) promoted by microwave irradiation, are reported. The efficient reaction process enabled us to rapidly access related natural product derivatives and to identify a new class of cytotoxic agents.

Strategies for the synthesis of novel indole alkaloid-based screening libraries for drug discovery.

A series of diverse indole-based chemotypes were synthesized from beta-tetrahydrocarboline (beta-THC) scaffolds prepared from commercially and readily available tryptamines and alpha-ketoesters. Diversity can be generated within these chemotypes through the following strategies: (a) appendage of substituents to the beta-THC scaffold, prepared in situ or as a template, through further elaboration and (b) skeletal modifications to the beta-THC scaffold via ring forming or ring breaking reactions. The strategies described here are amenable to high throughput solution-phase parallel synthesis, providing access to novel indole-based screening libraries for drug discovery.

Microwave-promoted Suzuki reactions of aryl chlorides in aqueous media.

[reaction: see text] The microwave-promoted Suzuki coupling reaction of aryl chlorides with boronic acids performed in an aqueous media was studied using the air- and moisture-stable catalyst POPd2 (dihydrogen di-mu-chlorodichlorobis(di-tert-butylphosphinito-kappaP)dipalladate (2-)). This catalyst system under microwave conditions (150 degrees C, 15 min) provided coupled products with yields ranging from 64% to 99%. This method tolerated a variety of substituents and sterically hindered substrates.

Development of alpha-keto-based inhibitors of cruzain, a cysteine protease implicated in Chagas disease.

Trypanosoma cruzi, a protozoan parasite, is the causative agent of Chagas disease, a major cause of cardiovascular disease in many Latin American countries. There is an urgent need to develop an improved therapy due to the toxicity of existing drugs and emerging drug resistance. Cruzain, the primary cysteine protease of T. cruzi, is essential for the survival of the parasite in host cells and therefore is an important target for the development of inhibitors as potential therapeutics. A novel series of alpha-ketoamide-, alpha-ketoacid-, alpha-ketoester-, and aldehyde-based inhibitors of cruzain has been developed. The inhibitors were identified by screening protease targeted small molecule libraries and systematically optimizing the P1, P2, P3, and P1' residues using specific structure-guided methods. A total of 20 compounds displayed picomolar potency in in vitro assays and three inhibitors representing different alpha-keto-based inhibitor scaffolds demonstrated anti-trypanosomal activity in cell culture. A 2.3A crystallographic structure of cruzain bound with one of the alpha-ketoester analogs is also reported. The structure and kinetic assay data illustrate the covalent binding, reversible inhibition mechanism of the inhibitor. Information on the compounds reported here will be useful in the development of new lead compounds as potential therapeutic agents for the treatment of Chagas disease and as biological probes to study the role that cruzain plays in the pathology. This study also demonstrates the validity of structure-guided approaches to focused library design and lead compound optimization.

Microwave-assisted acylation of 7-amino-5-aryl-6-cyanopyrido[2,3-d]pyrimidines.

A microwave-assisted method is described for monoacylating 7-amino-5-aryl-6-cyanopyrido[2,3-d]pyrimidines using excess acid chlorides in pyridine. A diacylated intermediate is effectively deacylated to the product amide by a macroporous-Tris resin. A small library of 17 amides was prepared to validate the method. The integration of commercial microwave technology into the ArQule chemistry platform is also discussed.