Designed, synthesized and biological evaluation of proteolysis targeting chimeras (PROTACs) as AR degraders for prostate cancer treatment.

As a continuation of our research on developing potent and potentially safe androgen receptor (AR) degrader, a series of novel proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were designed, synthesized and evaluated for their AR degradation activity against LNCaP (AR+) cell line. Most of the synthesized compounds displayed moderate to satisfactory AR binding affinity and might lead to antagonist activity against AR. Among them, compound A16 exhibited the best AR binding affinity (85%) and degradation activity against AR. Due to the strong fluorescence properties of pomalidomide derivatives, B10 was found to be effectively internalized and visualized in LNCaP (AR + ) cells than PC-3 (AR-) cells. Moreover, the molecular docking of A16 with AR and the active site of DDB1-CRBN E3 ubiquitin ligase complex provides guidance to design new PROTAC degrons targeting AR for prostate cancer therapy. These results represent a step toward the development of novel and improved AR PROTACs.

New Non-Nucleocide NS5B Protein Inhibitors for the Treatment of Chronic Hepatitis C Infection.

Hepatitis C virus is one of the major causative pathogens of chronic hepatitis and the second most common cause of hepatocellular cancer. The virally encoded NS5B RNA-dependent RNA polymerase is a vital component of the replicase complex that orchestrates the replication process leading to the production of progeny virus. In recent years, developing novel drugs to target NS5B polymerase has become one of the important strategies for the treatment of chronic hepatitis C infection. This review highlights the structure and scaffold of the non-nucleoside NS5B inhibitors represented in the past five years.

Efficient three-component one-pot synthesis of steroidal polysubstituted anilines.

An efficient and practical base-promoted cascade reaction has been developed to access steroidal polysubstituted anilines from simple precursors. The protocol reported herein achieved the formation of a benzene ring as well as three continuous C-C bonds in a single operation. The reaction mechanism was proposed on the basis of the key intermediate obtained. Besides, this method could be potentially employed for the synthesis of biphenyl compounds. The adjacent amine and nitrile groups existed in the final products have the potential for late stage functionalization, which would provide efficient access to steroidal compound collections with structural diversity and complexity.

Discovery of novel steroidal pyran-oxindole hybrids as cytotoxic agents.

A series of novel steroidal pyran-oxindole hybrids were efficiently synthesized in a single operation through the vinylogous aldol reaction of vinyl malononitrile 3 with substituted isatins involving the construction of C-C and C-O bonds. Some compounds displayed moderate to good cytotoxicity against T24, SMMC-7721, MCF-7 and MGC-803 cells. Compounds 4f and 4i were more potent than 5-Fu against T24 and MGC-803 cells with the IC50 values of 4.43 and 8.45 µM, respectively. Further mechanism studies indicated that compound 4i induced G2/M arrest and early apoptosis in a concentration- and time-dependent manner.

Synthesis and antimicrobial activities of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives.

A series of novel 1,2,4-triazolo [3,4-a] phthalazine derivatives were synthesized in five steps from a common precursor, phthalic anhydride. Most of synthesized phthalazine derivatives showed inhibitory activity against Staphylococcus aureus. One of phthalazine derivatives 5l showed inhibitory activity against all tested bacterial and fungal strains.

Synthesis of 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives and their cytotoxic activities.

A series of novel 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives were synthesized and characterized by NMR, HRMS. The pregnenolone (1) was first biotransformed by Mucor circinelloides var lusitanicus to 3beta, 7alpha, 11alpha-trihydroxy-pregn-5-en-20-one (3), then 3 was treated with various benzaldehydes to produce 3beta, 7alpha, 11alpha-trihydroxy-pregn-21-benzylidene-5-en-20-one derivatives. These derivatives showed remarkable activity against EC109 cells. The absolute configuration of 3 was also confirmed by signal-crystal X-ray analysis.

[Microbial transformation of 4-ene-3-one steroids by Mucor racemosus].

A steroid-converting fungus isolated from soil samples, was identified as Mucor racemosus according to its morphological characters. The application of M. racemosus for biotransformation of 4-ene-3-one steroids had been investigated to obtain hydroxylated derivatives of 4-ene-3-one steroids. The substrates were incubated with M. racemosus in rotary shaker (220 rpm) culture for a period of four days at 27 degrees C. All of the fermentation media were exhaustively extracted with ethyl acetate and filtered to separate the both from the mycelium. The transformation products were separated on silica gel column chromatography. Each microbial metabolite was characterized by spectroscopic methods such as IR, MS and NMR. Fermentation of progesterone yielded 14alpha-hydroxypregn-4-en-3, 20-dione and 7alpha, 14alpha-dihydroxypregn-4-en-3, 20-dione. Incubation of androstenedione resulted in three transformation products: 14, 17-dihydroxyandrost-4-en-3-one, 14alpha, 17beta-dihydroxyandrost-4-en-3-one and 6alpha, 17beta-dihydroxyandrost-4-en-3-one. This fungus was found to biotransformation steroids. The results showed that the fermentation of 4-ene-3-one steroids with M. racemosus yielded mainly 14alpha-hydroxy steroids.