Anticancer Effects Of Rosin-derivatives With Different Mechanisms And Endomorphin Analogucs Containing (Map) Without Cellular Tolerance And Dependence

Cancer still remains a threat to men’s health, representing the second leading of death worldwide. In this paper, the anticancer activity of novel rosin-derivatives introducing indicated side chains at position C18 of dehydroabietic acid (DHAA) was reported. Gratifyingly, all of these derivatives showed significantly cytotoxicity toward diverse human carcinoma cell lines. We found the compound 4 could induce cell membrane damage at high concentration as well as cell apoptosis at low concentration. However, compound 5, attachment of quinidine to dehydroabietic acid via thiourea bond, only induced apoptotic cell death. In addition, all these active compounds induced apoptosis mainly through mitochondrial-dependent pathway. Interestingly, compound 5 exhibited the highest anticancer activity and little toxicity to normal cells compared with the other derivatives. Therefore,5 merits further investigation as a potential agent for future anticancer treatment.In most cancer patients, pain is successfully treated with pharmacological measures using opioid analgesics for moderate to severe pain alone or in combination with adjuvant analgesics. So a new class of Endomorphin analogues was synthesized by introduction of novel unnatural a-methylene-β-amino acids (Map) at position 3 or/and 4. Futhermore, new EMs analogues containing Dmt1,(R/S)-βPro2, and (ph)Map4/(2-furyl)Map4 were described here. Their binding and functional activity were determined and compared. Many of these analogues showed higher binding affinities to μ-opioid receptor than EMs. Examination of cAMP accumulation and EKR1/2 phosphorylation in HEK293 cells confirmed the agonist properties of these analogs. Among the new analogues, Dmt1-(R)-βPro2-Trp3-(2-furyl)Map4 (analogue 8) displayed the highest affinity toward MOR in picomolar range (Kiμ=3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency in subpicomolar range (EC50= 0.0420 pM, ax = 99.5%). EKR1/2 phosphorylation assays were then carried out to demonstrate the degree of receptor desensition, endocytosis and resensition promoted by these analogues. We found that, campared with EM-1, this analogue also displayed the same degree of receptor desensition and endocytosis and hibited profoundly receptor resensition. These results suggested that this analogue may be of great importance in potential application as drug candidate for pain relief.