Diterpenoids with an unusual tricyclo[10.3.0.02,9]pentadecane skeleton from Pedilanthus tithymaloides as multidrug resistance modulators.

Three new diterpenoids with an unusual carbon skeleton, pedilanins A-C (1-3), and nine new jatrophane diterpenoids, pedilanins D-L (4-12), along with five known ones (13-17), were isolated from Pedilanthus tithymaloides. Compounds 1-3 characterize an unprecedented tricyclo[10.3.0.02,9]pentadecane skeleton. Compounds 4-8 are rare examples of the jatrophanes bearing a cyclic hemiketal substructure. Their structures were determined by an extensive analysis of HRESIMS, NMR, quantum-chemical calculation, DP4+ probability, and X-ray crystallographic data. In the bioassay, compounds 1-12 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 17.9 to 396.8 at the noncytotoxic concentration of 10 µM. The mechanism results indicated that compounds 2 and 3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.

Artificial nondirectional site-specific recombination systems.

Site-specific recombination systems (SRSs) are widely used in studies on synthetic biology and related disciplines. Nondirectional SRSs can randomly trigger excision, integration, reversal, and translocation, which are effective tools to achieve large-scale genome recombination. In this study, we designed 6 new nondirectional SRSs named Vika/voxsym1-4 and Dre/roxsym1-2. All 6 artificial nondirectional SRSs were able to generate random deletion and inversion in Saccharomyces cerevisiae. Moreover, all six SRSs were orthogonal to Cre/loxPsym. The pairwise orthogonal nondirected SRSs can simultaneously initiate large-scale and independent gene recombination in two different regions of the genome, which could not be accomplished using previous orthogonal systems. These SRSs were found to be robust while working in the cells at different growth stages, as well as in the different spatial structure of the chromosome. These artificial pairwise orthogonal nondirected SRSs offer newfound potential for site-specific recombination in synthetic biology.