Biological Evaluation For Cancer Therapy Based On Total Synthesized 7-Hydroxyneolamellarin A

Due to the abnormal structure of tumor vessels,tumor tissue always stay in hypoxic and acid condition.The activated hypoxia-inducible factior-1（HIF-1）signaling pathway could further activate the dow n-stream genes,which are related to tumor progress,such as boosting tumor cells migration,invasion and proliferation.Therefore,the exploitation of efficient and low cytotoxic inhibitors targeting HIF-1 signaling pathway has pressed an urgent clinical need.7-Hydroxyneolamellarin A（7-OH-Neo A）were extracted from sponge Dendrilla nigra.In vitro results demonstrated that 7-OH-Neo A had the capacity of inhibiting HIF-1 signaling pathway and down-regulating the expression of VEGF.However,the anti-tumor activities and the mechanism of action on HIF-1 inhibition have not been verified yet.Previously,7-OH-Neo A was total synthesized with 0.4%overall yield via 12-step.The yield was low in deprotection,which needs to be paid more effort to optimize.In this study,we optimized the condition of deprotection.Under the condition of adding 5%Pd/C at 50%w/w and pyridine at the ratio of 0.5,7-OH-Neo A was synthesized under H₂ atmosphere.The overall yield was boosted to 10%finally.Based on the total synthesized 7-OH-Neo A,the anti-tumor activities of 7-OH-Neo A were evaluated systematically in vitro and in vivo.Under the safe concentration,7-OH-Neo A could attenuate the accumulation of HIF-1αprotein and inhibit vascular epidermal growth factor（VEGF）transcriptional activity,showing good HIF-1 inhibitroy activity.The inhibitory efficacy of 7-OH-Neo A on tumor angiogenesis,proliferation,migration and invasion was evaluated further on cellular level.More importantly,7-OH-Neo A exhibited well biocompatibility and profound anti-tumor effect in breast cancer model by suppressing the accumulation of HIF-1αin tumor tissue.Last but not least,through molecular biological techniques and computer aided docking studies,we speculated that the target protein of 7-OH-Neo A was Hsp90.The analysis on binding mode between Hsp90 and 7-OH-Neo A was informative for derivatives design,aiming to explore more HIF-1 inhibitors with higher efficiency.