-Discovery and development of drug candidates through total syntheses and synthetic modifications of bioactive natural products focused on antitumor and anti-HIV agents.

-Study on cultivation and quality evaluation of medicinal plants (herbal medicines)



A) Isolation and identification of bioactive natural products from plants

We hypothesize that numerous unidentified bioactive small molecules are present in untouched plants, particularly those originating in rainforest areas, which are disappearing rapidly due to both human causes and climate changes. Thus, new drug candidates can be expected from vigorous exploration of carefully de-replicated plant resources.

B) Total syntheses of bioactive natural products such as flavonoids, terpenoids, macrolide lactones and alkaloids.

The limited availability of a natural source often impedes the further biological evaluation of bioactive natural products. Synthetic studies can provide dependable amounts of the bioactive compound, as well as readily provide new modified preclinical drug candidates.

C) Design, synthesis and structure-activity relationship of bioactive natural products.

Because chemical modification of lead compounds can enhance desired biological activities, improve bioavailability, or reduce adverse actions, this process has produced numerous effective drug candidates in clinical use or trials. Structure-activity relationship (SAR) studies using chemical modification are also important to establish the essential pharmacophore(s) of a drug candidate. They determine the structural features of a compound class that are essential for and important to biological activity.

D) Mechanisms of action study for promising antitumor agents by collaboration and discussion with biologists.

Determination of the cellular target of bioactive agent contributes significantly to the mechanism of action and SAR studies at the molecular level. We design and synthesize photoaffinity- or biotin-labeled bioactive agents to identify the cellular target.

We have successfully used this medicinal chemistry approach in the design and synthesis of many lead natural compounds. Our current main focus is the discovery and development of antitumor agents targeting multidrug resistant (MDR) and tubulin.

A recent highlight: Desmosdumotins B

Desmosdumotins B was isolated from the roots of Desmos dumosus, which has been used in Chinese folk medicine as an antimalarial, insecticidal, antirheumatic, antispasmodic, and analgesic agent. The total syntheses were successfully achieved by our group.
Desmosdumotin B (DesB) analogs:
One of our main targets is overexpressed anomalous P-glycoprotein (P-gp) in MDR tumor cells including cancer stem cells. In a course of studies on synthetic modification of DesB, we have found that triethyl DesB analogs with a 6π system ring-B (TEDB-MDR) activate P-gp ATPase result in exhibiting significantly improved selective index (SI = IC50 of non-MDR/MDR) against MDR. Interestingly, DesB analogs with a 10π system ring-B (TEDB-TB) exhibit a dramatically different bioactivity profile, directly inhibiting tubulin polymerization in a broad range of tumor cells, including MDR cells.

E) Quality evaluation of herbal medicines by DNA analysis, chemical constituents, and activity.

To maximize the ability of herbal medicines, it is necessary to understand the quality of them. There are many factors to affect their quality because they go through several processes to be produced, such as cultivation, harvest, washing, and drying. We investigate their natural resource, DNA alignments, chemical constituents as well as the cultivation conditions in our Medicinal Plant Garden.

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