Enhanced Stability of the Pharmacologically Active Lactone Form of 10-Hydroxycamptothecin by Self-Microemulsifying Drug Delivery Systems.

10-Hydroxycamptothecin (HCPT) is a DNA inhibitor of topoisomerase I and exerts antitumor activities against various types of cancer. However, reversible conversion from a pharmacologically active lactone form to an inactive carboxylate form of HCPT and poor water solubility hamper its clinical applications. To overcome these shortcomings, we designed a fine self-microemulsifying drug delivery system (SMEDDS) for HCPT to effectively protect HCPT in its active lactone form as well as improving dissolution rates. A formulation of HCPT-SMEDDS that contained ethyl oleate, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and polyethylene glycol 400 (PEG400) was optimized by using the central composite design and response surface methodology. Following 1:100 aqueous dilution of the optimized HCPT-SMEDDS, the droplet size of resulting microemulsions was 25.6 ± 0.7 nm, and the zeta potential was - 15.2 ± 0.4 mV. The optimized HCPT-SMEDDS appeared to stabilize the lactone moiety of HCPT with 73.6% being present in the pharmacologically active lactone forms in simulated intestinal fluid, but only 45.7% for free HCPT. Furthermore, the physically stable formulation showed the active lactone form predominated in HCPT-SMEDDS (> 95%) for 6 months under the accelerated storage condition. Meanwhile, the optimized SMEDDS formulation also significantly improved dissolution rates and membrane permeability of the lactone form of HCPT. Therefore, HCPT-SMEDDS involved designing for the ease of manufacture, and provided a potent oral dosage form for preserving its active lactone form as well as enhancing the dissolution rate.

Myricetin antagonizes semen-derived enhancer of viral infection (SEVI) formation and influences its infection-enhancing activity.

BACKGROUND: Semen is a critical vector for human immunodeficiency virus (HIV) sexual transmission and harbors seminal amyloid fibrils that can markedly enhance HIV infection. Semen-derived enhancer of viral infection (SEVI) is one of the best-characterized seminal amyloid fibrils. Due to their highly cationic properties, SEVI fibrils can capture HIV virions, increase viral attachment to target cells, and augment viral fusion. Some studies have reported that myricetin antagonizes amyloid ß-protein (Aß) formation; myricetin also displays strong anti-HIV activity in vitro. RESULTS: Here, we report that myricetin inhibits the formation of SEVI fibrils by binding to the amyloidogenic region of the SEVI precursor peptide (PAP248-286) and disrupting PAP248-286 oligomerization. In addition, myricetin was found to remodel preformed SEVI fibrils and to influence the activity of SEVI in promoting HIV-1 infection. Moreover, myricetin showed synergistic effects against HIV-1 infection in combination with other antiretroviral drugs in semen. CONCLUSIONS: Incorporation of myricetin into a combination bifunctional microbicide with both anti-SEVI and anti-HIV activities is a highly promising approach to preventing sexual transmission of HIV.

Discovery of a Highly Potent and Novel Gambogic Acid Derivative as an Anticancer Drug Candidate.

BACKGROUND AND PURPOSE: Gambogic Acid (GA), a promising anti-cancer agent isolated from the resin of Garcinia species in Southeast Asia, exhibits high potency in inhibiting a wide variety of cancer cells' growth. Moreover, the fact that it is amenable to chemical modification makes GA an attractive molecule for the development of anti-cancer agents. METHODS: Gambogic acid-3-(4-pyrimidinyloxy) propyl ester (compound 4) was derived from the reaction between 4-hydroxypropoxy pyrimidine and GA. Its structure was elucidated by comprehensive analysis of ESIMS, HRESIMS, 1 D NMR data. Anti-tumor activities of compound 4 and GA in vitro against HepG-2, A549 and MCF-7 cells were investigated by MTT assay. FITC/PI dye was used to test apoptosis. The binding affinity difference of compound 4 and GA binding to IKKß was studied by using Discovery Studio 2016. RESULTS: Compound 4 was successfully synthesized and showed strong inhibitory effects on HepG-2, A549 and MCF-7 cells lines with an IC50 value of 1.49±0.11, 1.37±0.06 and 0.64±0.16µM, respectively. Molecular docking study demonstrated that four more hydrogen bonds were established between IKKß and compound 4, compared with GA. CONCLUSION: Our results suggested that compound 4 showed significant effects in inducing apoptosis. Further molecular docking study indicated that the introduction of pyrimidine could improve GA's binding affinity to IKKß. Compound 4 may serve as a potential lead compound for the development of new anti-cancer drugs.