Total synthesis and stereochemical assignment of rakicidin F.

Total synthesis of rakicidin F was accomplished in 20 linear steps (0.68% overall yield), which enabled the configural determination of its six stereogenic centers as 2R, 15R, 16R, 17S, 19S, and 21S. The macrolactonization of the rakicidin linear precursor was investigated and the unsuccessful results might be attributed to the steric hindrance near C16-OH.

Total Synthesis and Determination of the Absolute Configuration of Rakicidin C.

The absolute configuration of rakicidin C was predicted by comparison of optical rotation data and absolute configuration of APD-cyclic depsipeptides and further determined by total synthesis. The absolute configuration of five chiral centers was determined as 2R, 15R, 16R, 17S, and 19S. Our efficient route involves 19 longest linear steps with an overall yield of 1.49%.

Total Synthesis and Structure Revision of Boholamide A.

The 15-membered cyclic depsipeptide boholamide A and an epimer were prepared by total synthesis for the first time, thus leading to a revision of C6 stereochemistry in the originally proposed structure of natural boholamide A. This convergent route features achievement of a macro-lactamization step in a gram scale. The revised boholamide A was sythesized with 16 linear steps in 5.46% overall yield. This work facilitates the investigations of boholamide A as a potential hypoxia-selective anticancer agent.

Synthesis and structure-activity relationship studies of parthenolide derivatives as potential anti-triple negative breast cancer agents.

Triple-negative breast cancer (TNBC) is the most aggressive cancers with a high recurrence rate and rapidly acquired drug resistance among various breast cancer subtypes. There is no specific drug for treatment of TNBC. Discovery of therapeutic agents with unique modes of actions is urgently needed. In this study, a series of seventy parthenolide derivatives was designed, synthesized, and evaluated for their anti-TNBC activities. Compound 7d exhibited the most potent activity against different breast cancer cells with IC50 values ranging from 0.20 µM to 0.27 µM, which demonstrated 11.6- to 18.6-fold improvement comparing to that of the parent compound parthenolide with IC50 values of 2.68-4.63 µM. It is worth to note that 7d was more active than the positive control drug ADR. Moreover, compound 7d could induce apoptosis of SUM-159 cells through mitochondria pathway and cause G1 phase arrest of SUM-159 cells. These findings indicate that compound 7d deserves further studies as a lead compound for ultimate discovery of effective anti-TNBC drug.

Synthesis of Cucurbitacin B Derivatives as Potential Anti-Hepatocellular Carcinoma Agents.

Cucurbitacin B shows potent activity against tumor cells, but its high toxicity limits its application in the clinic. A series of cucurbitacin B derivatives was synthesized and evaluated for their anti-hepatocellular carcinoma (HCC) activities against the HepG-2 cell line. These compounds were also tested for their toxicity against the L-O2 normal cell line. The compound with the most potential, 10b, exhibited potent activity against the HepG-2 cell line with an IC50 value of 0.63 µM. Moreover, compound 10b showed the highest TI value (4.71), which is a 14.7-fold improvement compared to its parent compound cucurbitacin B. A preliminary molecular mechanism study of 10b indicated that 10b could inhibit P-STAT3 to induce the activation of mitochondrial apoptotic pathways. An in vivo acute toxicity study indicated that the compound 10b has preferable safety and tolerability compared with cucurbitacin B. These findings indicate that compound 10b might be considered as a lead compound for exploring effective anti-HCC drugs.