The Synthesis And Preliminary Activity Assay In Vitro Of ML Derivatives As Anticancer Drug

Melatonin(melatonin,ML)is a neuroendocrine hormone of the human body,with high lipophilicity,can be dissolved in an aqueous solution,and acting on the cells by acrossing the cell membranes and nuclear membranes.So it widely played an important role in tissue cells.At present,a large number of studies have shown that the ML had a wide range of important physiological and pharmacological functions,regulating the reproductive system,immune system,nervous system and cardiovascular system;inhibiting a variety of biological reproductive function;enhancing the organism's immune function,and also having sedation,sedative and hypnotic.Otherwise,it had a significant inhibitory effect on malignant,and its anti-tumor mechanisms are complex and extensive.It had a completely different mechanism with others:affecting estrogen and Ca2+ signal transduction,inhibiting cell proliferation,changing the cell cycle and promoting apoptosis,inhibiting telomerase activity and anti-oxidation.Anticancer drugs were towards to discovering the drugs with lower toxicity and finding other mechanisms or multi-target mechanism drugs.Melatonin derivatives give a promise of looking for the better anticancer drugs by virtue of its unique antineoplastic mechanisms.With the developing of life sciences,it has been proven the two-way information transmission mechanism between among the nervous,endocrine and immune systems.They have many similarities:molecules information and cell surface markers,cyclical changes,positive and negative regulation feedback mechanism as well as the relationships between gender and aging,which form the regulating network by influencing each other,the mode of treating tumor is also gradually moving towards to multivariate and comprehensive biological treatment mode.Melatonin derivatives played the anti-tumor effect by acting with the neuroendocrine-immunity-cancer network.Melatonin can regulate the body's own immune system by acting with specific melatonergic ligands on the cell membrane of immune organs,and clear the tumor by regulating endogenous immunoreactive substances.Based on the structural characteristics of melatonin,three types of melatonin derivatives were synthesize.Through analysising and summarying the structural features of the known melatonin derivatives,we get its characteristics:the aromatic Hity ring was the skeleton structure,methoxy group side chain was the necessary group,in addition,the lipophilic side chain was a key activity of the compounds,the spatial distance between the methoxy side chain and lipophilic group was the important factor.According to its structural features and structure-activity relationships,we designed drug and transformate structure to find a better antineoplastic activity of ML derivatives.In this paper,the main research contents were summarized as follows:1.Three series of ML derivatives thiourea,tertiary amines and hydroxamic acids were designed regarding ML as lead compound.ML derivatives of thiourea were based on holding the original ML pharmacodynamic configuration,replacing acylamide groups by acylthiourea using isosteric design principles,increasing the electron density,and expecting to improve its affinity for the receptor.According to the laboratory preliminary study results showed that:the antineoplastic activity is better when introducing an aromatic group or an aromatic alkyl group on amine of 5-methytryptamine.The ML derivatives of tertiary amines were designed by introducing amide group combining the theory and the structure of ML pharmacodynamic model.ML derivatives of hydroxamic acids were a class of ML derivatives targeting on melatonin receptor and histone deacetylase.2.Three types of ML derivatives were synthesized and confirmed their chemical structure by 1HNMR and ESI-MS.44 compounds were the new structures and no reported in the literature.3.The antineoplastic activities of ML derivatives of thiourea were carried on the mice lymphocytic leukemia cell line L1210 by the MTT,and finding the antineoplastic activities of W-11 and W-13 were better.4.The results of the preliminary bioactivity assays of ML derivatives of thiourea were carried in vitro test show acyl thiourea group can improve its anti-tumor activity.In the other side,their antineoplastic activities were significant impacted the length of acyl group alkyl chain.The antineoplastic activities were bad,when the length of the alkyl chain is from 4 to 5 C atoms or more than 10 C atoms.