Studies On Synthesis And Biological Activities Of 2, 4-diaryl-1, 3-dithiolanes Compounds

Nitric Oxide (NO), an important biological messager and neurotransmitter, is involved in various physiological and pathological processes. Dysfunction of NO formation has been implicated in the pathogenesis of a number of disorders. NO is naturally generated from L-arginine by NO synthases (NOS). Three isoforms of NOS (eNOS, nNOS and iNOS) have been isolated and characterized. iNOS is responsible for the overproduced NO in macrophages and other cells after exposure to IFN-γand/or LPS, leading to inflammatory diseases such as asthma, septic shock and arthritis. Therefore, iNOS selective inhibitors may have potential clinical value due to blocking overproduction of NO. Platelet-activating factor (PAF) is a potent inflammatory mediator with a wide variety of biological activities. PAF exerts physiological functions by binding cell surface receptor. PAF receptor antagonists can block PAF –receptors and have potential clinical application.The roles of PAF and iNOS are synergetic in a lot of inflammatory disorders. So it can be assumed that a single compound effectively inhibiting the action of both PAF and NO may offer certain therapeutic advantages in terms of efficacy and pharmacodinamics over agents that inhibit either mediators alone.Based on the previous studies, the groups with iNOS inhibitory moieties such as isothiourea, guanidine and amidine were incorporated into the structure of PAF receptor antagonist, totally sixty-eight target compounds were designed and synthesized. The main objective of this work has been to develop iNOS/PAF dual inhibitors which are expected to treat septic shock and other inflammatory diseases. All target compounds are novel ones, and their structures were identified by IR, 1HNMR, MS and elemental analysis.The thesis is composed of following four parts:1. Review of NOS inhibitors and PAF antagonists NO and NOS inhibitors So far NOS inhibitors are derivatives of amino acid and nonamino acids, which have been structurally classified into compounds containing guanidine, isothiourea and amidine, etc. Two iNOS inhibitors have been in phase III of clinical trials. PAF and PAF antagonists PAF receptor antagonists come from two sources: one is natural compounds and the other synthetic compounds. The later has been classified into three categories:1) synthetic compounds derived from natural products 2) PAF analogs containing quaternary ammonium 3) heterocyclic compounds containing nitrogen. More than ten PAF receptor antagonists have been in phases II and III of clinical studies, and one has been marketed. Design, Synthesis and Discussion of Results Design of target compoundsIt was reported that compounds formed by incorporation of urea moiety into 2-aryl of dithiolane compounds can inhibit PAF and iNOS. Therefore, we designed and synthesized 12 dithiolane thiourea and substituted thiourea compounds(I 1-12). Some dithiolane amide compounds have been demonstrated to antagonize PAF receptors and to inhibit iNOS expression, so we synthesized 11 dithiolane amides (II 1-11) to investigate their different effects on iNOS inhibitory and PAF antagonistic activities. Isothiourea compounds have been showed strong iNOS inhibitory activity. So we introduced isothiourea moiety into 2-aryl of dithiolane compound and 24 isothiourea compounds(III 1-24) were synthesized. Since guanidine compounds have good iNOS inhibitory activity, so we introduced guanidine moiety into 2-aryl of dithiolane compounds and 8 guanidine deriviatives(IV 1-8) and 2 cycloguanidine derivatives(IV9-10) were synthesized.A lot of amidine compounds possess NOS inhibitory activity, some of which showed selectivity against iNOS, so we incorporated amidine moiety into 2-aryl of dithiolane compounds and 6 imidine derivatives(V1-6) were syntheized.Synthetic stratigiesThe key intermediator amino compounds were prepared starting from 3,4,5-trimethoxybenzaldehyde via epoxidation, reaction with excess xanthate, followed by reduction, cyclization and red...