【摘 要】
：
In cancer treatment,using a single drug directed towards just one target/mechanism is usually inadequate and overtime disease management usually requires drug combinations targeting multiple cancer pa
【机 构】
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Drug Discovery Pipeline,Guangzhou Institutes of Biomedicine and Health,Science City,Guangzhou 510530
【出 处】
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第五届岭南有机化学论坛暨华南理工大学-兰州大学有机化学双边论坛
论文部分内容阅读
In cancer treatment,using a single drug directed towards just one target/mechanism is usually inadequate and overtime disease management usually requires drug combinations targeting multiple cancer pathways to sustain efficacy.Choosing the right combination of chemotherapeutic agents is crucial for maximizing progression free survival while minimizing side effects.A series of novel anti-cancer agents were designed and synthesized based on coupling of different non-steroidal anti-inflammatory drugs(NSAIDs) with the epidermal growth-factor receptor(EGFR) tyrosine kinase inhibitor,erlotinib.Both the anti-proliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines.Among the derivatives made,compounds 10a,10c and 21g showed superb potency,comparable to that of erlotinib.Furthermore,preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus,superior anti-cancer activity was achieved.Finally,the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed,releasing both erlotinib and the specific NSAID in a time dependent manner.
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