Design, Synthesis And Biological Evaluation Of Cycloberberine And Sansanmycin A Derivatives

In continuation of our ongoing research on different biological activities of BBR analogues, due to well understanding of a related organic reaction, a novel compound-cycloberberine (CBBR) was constructed successfully and then confirmed by MS,1H NMR and13C NMR. Because of its planar structure, which could enhance antiproliferative potency via intercalating into DNA easily, CBBR might have a significant antiproliferative activity. The biological tests showed that the IC50of CBBR against HepG2cells was1.2μM.Taking CBBR as a lead compound because of its good activity and original structure,58new derivatives were designed and synthesized through modification of rings A, C, D and E. After measuring the inhibition rate of HepG-2cells, the structure-activity relationship (SAR) of this group of compounds were ascertained.(1) After the introduction of the ring E in BBR structure, with increase of the plane of the molecule, CBBR exhibited moderate activity;(2) An appropriate volume of group substituting at the8-position of ring D increased the anti-tumor activity;(3) The analogues substituted methylenedioxy or1,2-dimethoxy group in ring A had a significant antiproliferative activity;(4) Introduction of benzyl at the13-position improved the inhibitory activity;(5) The N+was essential, and removing the double bonds in ring C lead to disappearance of activity.By screening, compounds A-34、A-35、A-55、A-58、A-40、A-49and A-56showed a increased antiproliferative activity against HepG2with inhibition rate above85%at0.6μg/mL. The IC50of these derivatives against HepG2ranged from0.13to1.01μM, while it ranged from0.09to5.61μM against HCT116cells. Moreover, compound A-35exhibited anti-tumor effect against MCF-7/ADrR cells with an IC50of3.66μg/mL. So we could draw a conclusion that cross drug-resistance between CBBR and doxorubicin might not exist.Cell cycle analysis of the DNA profile in the HCT116verified that A-35resulted in a distinct accumulation of cells in the G2/M phase. The mechanism research revealed that A-35displayed a significant inhibitory activity against Top I and Top II at the concentration of15μg/mL. Besides, through the docking software-eHiTS, the docking models of A-35and the Top I-DNA or Top II ATPase domain were obtained. Consequently, we considered CBBR analogues to be a new class of Top I and Top II dual inhibitor.The acute toxicity in mice was tested and the results showed the LD50was more than500mg/kg (ip).Meanwhile, a series of sansanmycin (SSA) derivatives were designed and synthesized. SSA isolated from Streptomyces sp SS in our institute is a new uridyl-peptide antibiotic which exhibited moderate inhibitory effect against H37Ra, H37Rv and multidrug-resistant strains1279,2062,2199(MIC=10-40μg/mL). What’s more, the LD50was more than2400mg/kg (iv) in rats.However, natural SSA could not become antitubercular drug due to its weak activity. In order to improve its antitubercular effect,17derivatives were designed, semi-synthesized and evaluated for their activities with SSA as the lead compound. After measuring the MIC of drug-sensitive M. tuberculosis H37Rv, the SAR of this group of compounds were ascertained.The compound Id substituting isopropyl group at N-terminal displayed high potency against H37Rv, while compound la bearing dimethyl group at N-terminal was equal in potency to the SSA. The analogue1d was then assayed for effect against multidrug-resistant M. tuberculosis2199. Interestingly, the compound1d exhibited better inhibitory effect against multidrug-resistant M. tuberculosis2199than the natural product.