Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.

Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction of piperazine with newly generated 4-chloromethyl-2-amino thiazoles led to the desired piperazine thiazole compounds with high purities and good overall yields. Using a variety of commercially available carboxylic acids, the parallel synthesis of a variety of disubstituted 4-(piperazin-1-ylmethyl)thiazol-2-amine derivatives is described. the screening of the compounds led to the identification of antiplasmodial compounds that exhibited interesting antimalarial activity, primarily against the Plasmodium falciparum chloroquine-resistant Dd2 strain. The hit compound 2291-61 demonstrated an antiplasmodial EC50 of 102 nM in the chloroquine-resistant Dd2 strain and a selectivity of over 140.

Polyheterocyclic peptidomimetics: Parallel solid phase synthesis of oligo cyclic guanidines and their inhibition activity against Mycobacterium tuberculosis DNA gyrase.

Polyheterocycles are one of the most desired synthetic targets due to their numerous and valuable applications in various fields. We report the design and the parallel synthesis of novel linear oligocyclic guanidine peptidomimetics from predesigned reduced polyamides. A screening of these compounds identified active Mycobacterium tuberculosis DNA gyrase inhibitors which do not inhibit human DNA topoisomerase IIα and topoisomerase I.

From citronellal to iridoids: asymmetric synthesis of iridoids and their analogues via organocatalytic intramolecular Michael reactions.

A series of iridoids, including iridomyrmecin A, B, C', D', (-)-isoiridomyrmecin, (+)-7-epi-boschnialactone, and the inside-yohimbine analogues have been synthesized from readily available, naturally occurring (-)-citronellal via the key step reaction of metathesis, organocatalysis, and subsequent transformations, such as reduction, lactonization, alkylation, Pictet-Spengler reaction and lactamization. Notably, the use of DBU as an additive in the organocatalytic intramolecular Michael reaction of an aldehyde ester with Jørgensen-Hayashi catalysts resulted in better stereoselectivity than the conditions using acetic acid as an additive. The structures of three products have been unequivocally established with single-crystal X-ray crystallographic analyses.

Asymmetric Synthesis of Spirocyclopentane Oxindoles Containing Four Consecutive Stereocenters and Quaternary α-Nitro Esters via Organocatalytic Enantioselective Michael-Michael Cascade Reactions.

An enantioselective domino Michael-Michael reaction of nitroolefins and 2-nitro-3-arylacrylates has been established, which provided a series of spirocyclopentane oxindoles with four consecutive stereocenters including quaternary α-nitro esters with good yields (up to 73%) and excellent enantioselectivities (up to 97% ee). The reaction was realized and optimized with the aid of a chiral squaramide-amine catalyst. The structures of 11 products were confirmed by single-crystal X-ray diffraction analysis.

The azatryptophan-based fluorescent platform for in vitro rapid screening of inhibitors disrupting IKKß-NEMO interaction.

The nuclear factor-κB (NF-κB) plays an important role in inflammatory and immune responses. Aberrant NF-κB signaling is implicated in multiple disorders, including cancer. Targeting the regulatory scaffold subunit IκB kinase γ (IKKγ/NEMO) as therapeutic interventions could be promising due to its specific involvement in canonical NF-κB activation without interfering with non-canonical signaling. In this study, the use of unnatural amino acid substituted IKKß with unique photophysical activity to sense water environment changes upon interaction with NEMO provides a powerful in vitro screening platform that would greatly facilitate the identification of compounds having the potential to disrupt IKKß-NEMO interaction, and thus specifically modulate the canonical NF-κB pathway. We then utilized a competitive binding platform to screen the binding ability of a number of potential molecules being synthesized. Our results suggest that a lead compound (-)-PDC-099 is a potent agent with ascertained potency to disrupt IKKß-NEMO complex for modulating NF-κB canonical pathway.

Organocatalytic Enantioselective Michael-Michael-Michael-Aldol Condensation Reactions: Control of Six Stereocenters in a Quadruple-Cascade Asymmetric Synthesis of Polysubstituted Spirocyclic Oxindoles.

An organocatalyzed enantioselective Michael-Michael-Michael-aldol cascade reaction for the construction of cyclopentane fused spirooxindoles was achieved. The domino reaction provided the spirooxindoles with six contiguous stereocenters including a quaternary center in good yields (55-64%) with excellent enantioselectivities (up to >99% ee). Enantioselective Michael-Michael-Michael-aldol condensation-aromatization reactions of an isomeric product were observed.

Treatments for microcystic adnexal carcinoma--A review.

INTRODUCTION: Microcystic adnexal carcinoma (MAC) is a rare malignant cutaneous neoplasm presenting as a slow-growing, indurated nodule, papule or plaque. Clinically, the lesion can blend into the surrounding skin, obscuring borders and consequently delaying diagnosis histologically. Surgical and histologic techniques that emphasize examination of all margins may optimize management through early diagnosis and prevention of recurrences. OBJECTIVE: This review aims to assess the current surgical and histology techniques that result in lower rates of tumor recurrence and, consequently, better clinical outcomes. METHODS: A literature search of the PubMed database was conducted to identify studies examining wide local excision (WLE), Mohs micrographic surgery (MMS), radiotherapy (RT) and chemotherapy in the treatment of MAC. RESULTS: WLE had a high likelihood of positive margins and local recurrence. MMS was found to have the lowest recurrence rates. Definitive RT could be considered for elderly patients or those who are poor surgical candidates, as large surgical defects may be required to obtain free margins with either WLE or MMS. Chemotherapy was found to be ineffective. CONCLUSION: Complete margin evaluation with MMS permits complete tumor removal with subsequently low recurrence rate.