Zhenyuan Miao

Three-Dimensional Model of Lanosterol 14α-Demethylase from Cryptococcus neoformans: Active-Site Characterization and Insights into Azole Binding

ABSTRACT Cryptococcus neoformans is one of the most important causes of life-threatening fungal infections in immunocompromised patients. Lanosterol 14α-demethylase (CYP51) is the target of azole antifungal agents. This study describes, for the first time, the 3-dimensional model of CYP51 from Cryptococcus neoformans (CnCYP51). The model was further refined by energy minimization and molecular-dynamics simulations. The active site of CnCYP51 was well characterized by multiple-copy simultaneous-search calculations, and four functional regions important for rational drug design were identified. The mode of binding of the natural substrate and azole antifungal agents with CnCYP51 was identified by flexible molecular docking. A G484S substitution mechanism for azole resistance in CnCYP51, which might be important for the conformation of the heme environment, is suggested.

New tricks for an old natural product: discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure-activity relationship analysis and biological evaluations.

Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus . Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction.

The p53-MDM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K(i) = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K(i) = 260.0 nM) and 60a (K(i) = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development of novel antitumor agents.

Selection of evodiamine as a novel topoisomerase I inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents.

Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI inhibitors. Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate to good in vitro antitumor activity. These novel structures can be considered as good starting points for the development of new antitumor lead compounds. Hit 20 (evodiamine) was chosen for preliminary structure-activity relationship studies. Various groups, including alkyl, benzoyl, benzyl and ester, were introduced to the indole nitrogen atom of evodiamine. The substituted benzoyl groups were found to be favorable for the antitumor activity and spectrum. The 4-Cl benzoyl derivative, compound 29u, was the most active one with IC(50) values in the range 0.049-2.6 μM.

Chalcone: A Privileged Structure in Medicinal Chemistry

Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

New azoles with potent antifungal activity: Design, synthesis and molecular docking

In response to the urgent need for novel antifungal agents with improved activity and broader spectrum, computer modeling was used to rational design novel antifungal azoles. On the basis of the active site of lanosterol 14alpha-demethylase from Candida albicans (CACYP51), a series of new azoles with substituted-phenoxypropyl piperazine side chains were rational designed and synthesized. In vitro antifungal activity assay indicates that the new azoles show good activity against most of the tested pathogenic fungi. Interestingly, the designed compounds are also active against an azole-resistant clinical strain. Compared to fluconazole and itraconazole, several compounds (such as 12i, 12j and 12n) show higher antifungal activity and broader spectrum, which are promising leads for the development of novel antifungal agents.

Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents

A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery.

Design and synthesis of antifungal benzoheterocyclic derivatives by scaffold hopping

The incidence of invasive fungal infections and associated mortality is increasing dramatically. Although azoles are first-line antifungal agents, cross-resistance and hepatic toxicity are their two major limitations. The discovery of novel non-azole lead compounds will be helpful to overcome these problems. On the basis of our previously reported benzopyran non-azole CYP51 inhibitor, scaffold hopping was used to design structurally diverse new compounds and expand the structure-activity relationships of the lead structure. Five kinds of scaffolds, namely benzimidazole, benzoxazole, benzothiazole, quinazolin-4-one and carboline, were chosen for synthesis. In vitro antifungal activity data and results from molecular docking revealed that the scaffold was important for the antifungal activity. Several compounds showed potent activity against both standard and clinically resistant fungal pathogens, suggesting that they can serve as a good starting point for the discovery of novel antifungal agents.

Design, synthesis and antifungal activity of isosteric analogues of benzoheterocyclic N-myristoyltransferase inhibitors

N-myristoyltransferase (NMT) has been a promising new target for the design of novel antifungal agents with new mode of action. A series of benzoxazole and indole derivatives were designed and synthesized as isosteric analogues of benzoheterocyclic NMT Inhibitors. In vitro antifungal assay indicated that the benzoxazole derivatives were far more potent than the indoles. Molecular docking studies revealed that the hydrogen bonding interaction between the benzoheterocyclic core and NMT might be essential in the orientation of the inhibitor to a proper position. The antifungal activity of benzoxazole derivative 8f was comparable or superior to that of fluconazole, which can serve as a good starting point for further studies of structural diversity of the benzoheterocyclic NMT inhibitors.

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.