Yuyang Jiang

Copper-catalyzed domino synthesis of quinazolinones via Ullmann-type coupling and aerobic oxidative C-H amidation.

An efficient copper-catalyzed approach to quinazolinone derivatives has been developed, and the protocol uses cheap and readily available substituted 2-halobenzamides and (aryl)methanamines as the starting materials as well as economical and environmentally friendly air as the oxidant. This can be the first example of constructing N-heterocycles via sequential Ullmann-type coupling under air and aerobic oxidative C-H amidation.

Efficient Intermolecular Iron-Catalyzed Amidation of C−H Bonds in the Presence of N-Bromosuccinimide

We have developed an efficient, inexpensive, and air-stable catalyst/oxidant (FeCl2/NBS) system that could efficiently promote amidation of benzylic sp3 C-H bonds in ethyl acetate under mild conditions.

Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility

Significance How receptor for hyaluronan-mediated motility (RHAMM) expression is regulated, how statins exert anticancer effects, and what roles mevalonate and Hippo pathways play in tumors are important issues in cancer biology. We find that the two pathways converge onto Yes-associated protein (YAP)/TEAD to control RHAMM transcription leading to ERK activation and cancer metastasis, which is inhibited by simvastatin. YAP/TEAD binds RHAMM promoter at specific sites to activate RHAMM transcription, and mevalonate/simvastatin affects RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic distribution. These in vitro and in vivo findings identify a mechanism regulating RHAMM expression and cancer metastasis wherein RHAMM is a downstream effector of mevalonate/Hippo pathways, and a YAP/TEAD-transcription and simvastatin-inhibition target, revealing interesting interplay of the pathways and potential targets for cancer therapeutic agents. Expression of receptor for hyaluronan-mediated motility (RHAMM), a breast cancer susceptibility gene, is tightly controlled in normal tissues but elevated in many tumors, contributing to tumorigenesis and metastases. However, how the expression of RHAMM is regulated remains elusive. Statins, inhibitors of mevalonate metabolic pathway widely used for hypercholesterolemia, have been found to also have antitumor effects, but little is known of the specific targets and mechanisms. Moreover, Hippo signaling pathway plays crucial roles in organ size control and cancer development, yet its downstream transcriptional targets remain obscure. Here we show that RHAMM expression is regulated by mevalonate and Hippo pathways converging onto Yes-associated protein (YAP)/TEAD, which binds RHAMM promoter at specific sites and controls its transcription and consequently breast cancer cell migration and invasion (BCCMI); and that simvastatin inhibits BCCMI via targeting YAP-mediated RHAMM transcription. Required for ERK phosphorylation and BCCMI, YAP-activated RHAMM transcription is dependent on mevalonate and sensitive to simvastatin, which modulate RHAMM transcription by modulating YAP phosphorylation and nuclear-cytoplasmic localization. Further, modulation by mevalonate/simvastatin of YAP-activated RHAMM transcription requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement, but is largely independent of MST and LATS kinase activity. These findings from in vitro and in vivo investigations link mevalonate and Hippo pathways with RHAMM as a downstream effector, a YAP-transcription and simvastatin-inhibition target, and a cancer metastasis mediator; uncover a mechanism regulating RHAMM expression and cancer metastases; and reveal a mode whereby simvastatin exerts anticancer effects; providing potential targets for cancer therapeutic agents.

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting.

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.

Copper-catalyzed synthesis of benzimidazoles via cascade reactions of o-haloacetanilide derivatives with amidine hydrochlorides

We have developed an efficient method for the synthesis of benzimidazoles via cascade reactions of o-haloacetoanilide derivatives with amidine hydrochlorides. The protocol uses 10 mol % CuBr as the catalyst, Cs2CO3 as the base, and DMSO as the solvent, and no ligand is required. The procedure proceeds via the sequential coupling of o-haloacetoanilide derivatives with amidines, hydrolysis of the intermediates (amides), and intramolecular cyclization with the loss of NH3 to give 2-substituted 1H-benzimidazoles.

An Efficient One-Pot Copper-Catalyzed Approach to Isoquinolin-1(2H)-one Derivatives

A simple and efficient copper-catalyzed method for synthesis of 3,4-disubstituted isoquinolin-1(2H)-one derivatives via cascade reactions of substituted 2-halobenzamides with beta-keto esters under mild conditions has been developed, and the method has economical and practical advantages.

Copper-Catalyzed Synthesis of Quinazoline Derivatives via Ullmann-Type Coupling and Aerobic Oxidation

A simple and efficient copper-catalyzed approach to quinazoline derivatives has been developed, and the protocol uses readily available substituted (2-bromophenyl)methylamines and amides as the starting materials, and the cascade reactions were performed under air via sequential Ullmann-type coupling and aerobic oxidation without addition of any ligand or additive. The present method provides a convenient and practical strategy for synthesis of quinazoline derivatives.

General and efficient copper-catalyzed amidation of saturated C-H bonds using N-halosuccinimides as the oxidants

We have developed a general and efficient method for copper-catalyzed amidation of saturated C-H bonds under mild conditions, and the used substrates include benzylic reagents, the N, N-dimethylaniline derivatives, the free carboxamides, and sulfonamides. The protocol uses inexpensive and readily available CuBr/ N-halosuccinimide (NBS or NCS) as the catalyst/oxidant, so it provides practical applications for synthesis of various amides via C-H activation.

The effect of autophagy inhibitors on drug delivery using biodegradable polymer nanoparticles in cancer treatment.

Nanoparticles of biodegradable polymers (NPs) have been widely used for drug delivery. However, there has been little research on their fate after internalized into the cells. We show in this research by using docetaxel as a model anticancer drug, which is formulated in the cholic acid conjugated nanoparticles of poly(lactic-co-glycolic acid (PLGA NPs) that the NPs induce autophagy of the cancer cells and thus may hinder the advantages of the nanomedicine. Moreover, we show both in vitro and in vivo that co-administration of autophagy inhibitors such as 3-methyladenine (3-MA) and Chloroquine (CQ) could greatly enhance the therapeutic effects of the nanoparticle formulation. The IC50 values of the drug formulated in the PLGA NPs after 24 h treatment with no autophagy inhibitor or in combination with 10 mm 3-MA or 30 μm CQ are 38.27 ± 1.23, 6.7 ± 1.05, 4.78 ± 1.75 μg/mL, which implie 5.7 or 8,0 fold efficient by the autophagy inhibition respectively. Moreover, both the volume and the weight of the shrunk tumor of the mice after 20 day treatment with the PLGA NPs formulation combined with 3-MA or CQ are found to be only about a half in comparison with the treatment with the PLGA NPs formulation alone. In this research, we reported such a new mechanism of cancer cells to have PLGA NPs captured and degraded by auto-lysosomes. The findings provide advanced knowledge for development of nanomedicine for clinical application.

Copper-catalyzed coupling of tertiary aliphatic amines with terminal alkynes to propargylamines via C-H activation.

We have developed a convenient and efficient method for coupling of tertiary aliphatic amines with terminal alkynes to propargylamines via C-H activation. The protocol uses CuBr as the catalyst, NBS as the free radical initiator, CH(3)CN as the solvent, and the alkynylation was selectively performed on the methyl of tertiary aliphatic amines at 80 degrees C. This is an economical and practical method for the synthesis of propargylamines.