Synthesis And Biological Activities Of Novel Immunomodulators Design And Synthesis Of Novel Camptothecin Derivatives

PART I:Immunomodulators are a large class of biological or chemical substances that can regulate immune function, have important clinical roles in the treatment of the infectious diseases, the autoimmune diseases and the organ transplantation. Fingolimod (FTY720) has displayed favorable immunomodulatory activity in numerous investigations. Fingolimod is phosphorylated in vivo by sphingosine kinase2, and the active compound,(S)-FTY720-phosphate then binds to extracellular G protein-coupled receptors, S1P1,3,4,5receptor, and inhibit lymphocytes egress out of lymphoid organs. The latest researchs show, sphingosine kinase is an attractive target for hyper-proliferative disease therapy, fingolimod has been reported to have the capacity to inhibit sphingosine kinase enzymatic activity.Up to now, a large number of fingolimod analogs were synthesized. Based on SAR, the structural flexible carbon chain of fingolimod generates a vast number of conformations that can be a complicating factor in drug development, so conformational rigidification can be a very important strategy in drug design. To achieve effective rigidification, we selected the trans-4-alkyl-substituted cyclohexane, the1,2,3-Triazole and the4-alkyl-substituted phenyl to replace the flexible C8alkyl chain of fingolimod, respectively. Immunomodulatory activities and anti-tumor activities of these fingolimod analogues were tested. In this part, a new synthetic route was found to provide accessibility for the medicinal modification of Fingolimod analogues, and provide a guarantee for the industrialization of Fingolimod.PART II:Camptothecins are found to be an important class of topoismerase I inhibitor for DNA replication and transmission. The SAR shows that the closed lactone E-ring is essential for the anti-tumor activities of camptothecin and CPT derivatives. In order to improve the stability of the E-lactone ring of camptothecin derivatives and to achieve the structural diversity of camptothecins, a new class of seven-membered lactone ring of camptothecin analogues were first designed, but the results show that these compounds were also very unstable. Therefore, we designed CPT keto analogues with a a-hydroxylactone six-membered E-ring to solve the stability of the E ring. The synthesis of these compounds is still undergoing.Polyamines play crucial roles in a number of cell processes including cell proliferation and differentiation, and possess a variety of pharmacological properties. In this part, in order to improve the stability of the E-lactone ring of camptothecin derivatives and facilitate selective uptake by tumor cells, we also synthesized a series of CPT derivatives with a spermine chain linked to20-OH of CPT via succinate group. Anti-tumor activites of these CPT prodrugs in vitro and in vivo were evaluated.