Total Synthesis of Tricladins A and B and Identification of Their Absolute Configuration

A concise synthesis of both (<i>S</i>)- and (<i>R</i>)-enantiomers of tricladins A and B from l-Boc alanine was achieved. The diastereomeric intermediates were separated by chiral column chromatography, and the absolute configuration of the 2-position was assigned by observed NOE interactions with the known stereogenic center at the 5-position. By comparison of all synthesized final enantiomers with the corresponding natural products, we concluded that the natural tricladins A and B must have the (<i>R</i>)-configuration

Image1_Effects and mechanisms of natural alkaloids for prevention and treatment of osteoporosis.TIF

Natural alkaloids are polycyclic, nitrogen-containing, and basic compounds obtained from plants. In this review, the advances in bioactive alkaloids with respect to their chemical structures, herbal sources, and effects for the prevention and treatment of osteoporosis are discussed. Anti-osteoporosis alkaloids are classified into six categories based on the chemical structure, namely, isoquinoline alkaloids, quinolizidine alkaloids, piperidine alkaloids, indole alkaloids, pyrrolizidine alkaloids and steroidal alkaloids. They promote mesenchymal stem cells differentiation, improve osteoblast proliferation, stimulate osteoblast autophagy and suppress osteoclast formation. These natural alkaloids can regulate multiple signaling pathways, including interrupting the tumor necrosis factor receptor associated factor 6- receptor activator of nuclear factor kappa B interaction, inhibiting the nuclear factor kappa B pathway in osteoclasts, activating the p38 mitogen-activated protein kinases pathway in osteoblasts, and triggering the wingless and int-1 pathway in mesenchymal stem cells. This review provides evidence and support for novel drug and clinical treatment of osteoporosis using natural alkaloids.</p

Bifidenone: Structure–Activity Relationship and Advanced Preclinical Candidate

Bifidenone is a novel natural tubulin polymerization inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, we present here 42 analogues that were synthesized to examine the structure–activity relationship of bifidenone derivatives. In addition to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogues. Compounds <b>45b</b> and <b>46b</b> were found to demonstrate promising efficacy in murine xenograft experiments, and <b>46b</b> had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel