Shanchao Wu

Meeting Organocatalysis with Drug Discovery: Asymmetric Synthesis of 3,3′-Spirooxindoles Fused with Tetrahydrothiopyrans as Novel p53-MDM2 Inhibitors

An organocatalytic enantioselective Michael-Michael cascade reaction is developed for the synthesis of chiral spirotetrahydrothiopyrans. This highly functionalized scaffold was assembled in moderate to good yield (55-74%) and excellent diastereo- and enantioselectivities (>30:1 dr, ≥ 99% ee) with the creation of four consecutive stereogenic centers. The novel spiro-oxindole scaffold is validated as a new class of p53-MDM2 protein-protein interaction inhibitors with good antitumor activity.

Asymmetric Synthesis of Chiral Dihydrothiopyrans via an Organocatalytic Enantioselective Formal Thio [3 + 3] Cycloaddition Reaction with Binucleophilic Bisketone Thioethers

An unprecedented organocatalytic highly enantioselective approach to a 3,4-dihydro-2H-thiopyran scaffold with two contiguous stereogenic centers has been implemented through a formal thio [3 + 3] cycloaddition process involving a Michael-aldol condensation cascade sequence. Notably, a new class of binucleophilic bisketone thioethers is designed for the process. Furthermore, the fine-tuning of their reactivity enables the cascade process to proceed with highly regioselectively.

A new strategy to improve the metabolic stability of lactone: discovery of (20S,21S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase I inhibitors.

Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.

Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents.

In an effort to expand the structure-activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity.

Facile Assembly of Chiral Tetrahydrothiopyrans Containing Four Consecutive Stereocenters via an Organocatalytic Enantioselective Michael–Michael Cascade

An organocatalytic enantioselective Michael-Michael cascade reaction has been implemented for the creation of structurally variant chiral tetrahydrothiopyrans. The process is realized by employment of new bifunctional ketothioether enones and proceeds highly enantioselectively with formation of four consecutive stereogenic centers.

Novel benzothiazole derivatives with a broad antifungal spectrum: design, synthesis and structure–activity relationships

N-Myristoyltransferase (NMT) is a new target for the development of novel antifungal agents. The benzothiazole derivative FR1335 is a highly potent NMT inhibitor with fungicidal activity. However, FTR1335 was only active against Candida albicans and its antifungal spectrum and solubility remained to be improved. Thus, a series of benzothiazole derivatives were designed and synthesized by modifying the scaffold and side chain of FTR1335. Interestingly, the antifungal spectrum of the target compounds was significantly expanded and also new structure–activity relationship information was obtained. Particularly, compound 6m showed good inhibitory activity against a wide range of fungal pathogens including systemic fungus and dermatophytes. Its antifungal activity against Cryptococcus neoformans and Candida glabrata was higher than that of fluconazole. Moreover, compound 6m also exhibited in vivo antifungal activity in a Caenorhabditis elegans-Candida albicans infection model, which represents a promising lead for further optimization.

Tackling Fungal Resistance by Biofilm Inhibitors

The high incidence and mortality of invasive fungal infections and serious drug resistance have become a global public health issue. The ability of fungal cells to form biofilms is an important reason for the emergence of severe resistance to most clinically available antifungal agents. Targeting fungal biofilm formation by small molecules represents a promising new strategy for the development of novel antifungal agents. This perspective will provide a comprehensive review of fungal biofilm inhibitors. In particular, discovery strategies, chemical structures, antibiofilm/antifungal activities, and structure-activity relationship studies will be discussed. Development of inhibitors to treat biofilm-related resistant fungal infections is a new yet clinically unexploited paradigm, and there is still a long way to go to clinical application. Better understanding of fungal biofilms in combination with systematic drug discovery efforts will pave the way for potential clinical applications.

From Antidiabetic to Antifungal: Discovery of Highly Potent Triazole–Thiazolidinedione Hybrids as Novel Antifungal Agents

In an attempt to discover a new generation of triazole antifungal agents, a series of triazole–thiazolidinedione hybrids were designed and synthesized by molecular hybridization of the antifungal agent fluconazole and rosiglitazone (an antidiabetic). Most of the target compounds showed good to excellent inhibitory activity against a variety of clinically important fungal pathogens. In particular, compounds (Z)‐5‐(2,4‐dichlorobenzylidene)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)thiazolidine‐2,4‐dione) (15 c), (Z)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione (15 j), and (Z)‐3‐(2‐(2,4‐difluorophenyl)‐2‐hydroxy‐3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(furan‐3‐ylmethylene)thiazolidine‐2,4‐dione (15 r) were highly active against Candida albicans, with MIC80 values in the range of 0.03–0.15 μM. Moreover, compounds 15 j and 15 r were found to be effective against four fluconazole‐resistant clinical isolates; these two compounds are particularly promising antifungal leads for further optimization. Molecular docking studies revealed that the hydrogen bonding interactions between thiazolidinedione and CYP51 from C. albicans are important for antifungal activity. This study also demonstrates the effectiveness of molecular hybridization in antifungal drug discovery.

Discovery of 1-arylpyrrolidone derivatives as potent p53–MDM2 inhibitors based on molecule fusing strategy

Introducing an aryl moiety to our previous pyrrolidone scaffold by molecule fusing strategy afforded two sets of isopropylether-pyrrolidone and α-phenylethylamine-pyrrolidone derivatives. Two novel compounds 8b and 8g of the latter serial showed potent p53-MDM2 inhibitory activities with Ki values of 90nM which were three-time higher than that of the parent compound. We also confirmed compound 8b can activate p53 proteins in lung cancer A549 cells. The results offered us valuable information for further lead optimization.

Design, synthesis and evaluation of 4-substituted anthra[2,1-c][1,2,5]thiadiazole-6,11-dione derivatives as novel non-camptothecin topoisomerase I inhibitors

Previously, 4-tosylanthra[1,2-c][1,2,5]thiadiazole-6,11-dione (1) was identified as a novel non-camptothecin topoisomerase I (Top1) inhibitor by structure-based virtual screening. Herein, a series of 4-substituted derivatives were designed and synthesized. Most of them showed potent Top1 inhibitory activity. Their in vitro antiproliferative activity was also evaluated in A549, HCT-116 and ZR-75-30 human cancer cell lines. Compound 8s showed good antiproliferative activity with IC50 of 0.52μM and 0.42μM against HCT-116 and ZR-75-30 cell line, respectively. Top1 unwinding assay and molecular modeling studies rationalized the mode of action of this new class of inhibitors.