Synthesis Of Natural Product-inspired Functional Macrocyclic And Aza-polycyclic Molecules

Part ?:The Synthetic Methodologies and Biological Evaluation of Natural Product Inspired MacrocyclesMacrocycles are molecular structures that contain cyclic frameworks of at least twelve atoms,they widely exist in natural products and have been used in clinic studies for a long time.The macrocyclization of linear precursors contributes to restricted internal bond rotations and constrained conformations,which potentially improve the affinity and selectivity for protein targets.Furthermore,the specific three-dimensional conformation of macrocycles plays a critical role in flexible modulation of ADMET properties(bioavailability,metabolic stability,etc.)and membrane permeability.Hence,there is increasing interest in designing and constructing pseudo-natural macrocycles based on the characterized skeleton of natural macrocycles.Although the reported macrocyclization methods and strategies promoted the development of macrocycles synthesis,the limited chemical space of novel and multifunctional macrocycles is hard to meet the requirement of screening for biological targets.It is therefore highly desirable to develop novel methods and strategies to prepare macrocycles with structural diversity and multi-biofunction.In the second chapter of this paper,we have utilized the readily available building blocks(carboxylic acids,natural amino acids and vinylethylene carbonates)to develop a biomimetic modularization strategy for the construction of macrolides which efficiently surmount P-gp-mediated MDR in cancer chemotherapy.In order to obtain an efficient route for the construction of diverse macrocycles,we developed an Rh(III)-catalyzed native carboxylic acid-directed and solvent-free C-H activation allylation with high stereoselectivity and chemoselectivity,which displays mild conditions,broad substrate scope.We synthesized diverse poly-substituted allylic alcohol as a multifunctional and biomimetic building block,and this synthetic methodology was efficient even on 5 mmol scales.The biomimetic modularization strategy has efficiently access to 14-and 17-membered(Z)-allylic-supported or derivative macrolides by applied poly-substituted allylic alcohol to staple bipeptide or tripeptide through a successive amidation,hydrolysis and esterification.Additionally,the antidiabetic drug Repaglinide bearing allylic alcohol linker could efficiently react with dipeptide to achieve macrolide 4g.These(Z)-allylic-supported macrolides were screened in different test systems and they exhibited excellent potency as an inhibitor of P-gp-mediated MDR in tumor cell lines.In vitro experiments showed that these macrolides significantly restored the sensitivities of drug-resistant tumor cell lines by inhibiting P-gp transporter function,and the activity of 4g with 176-fold in reversals is much more potent than that of the first-generation P-gp inhibitor verapamil.In this section,a biomimetic modularization strategy to create functional macrolides through C–H activation allylation is described and it provide valuable sources for the developing inhibitors of P-gp to reverse the MDR in cancer chemotherapy and the exploration of diverse macrocycles.In the third chapter of this paper,photoinduced remote C(sp³)-H acylation are described.In the beginning,we set out to develop the photoredox-mediated intermolecular acylation and the acyl radical generated from aldehydes.This reaction offers a mild condition,wide substrate scope and good functional group compatibility.Furthermore,this acylation could be conducted on a gram-scale(80 folds)without flow photochemical equipment.Additionally,our mechanistic studies suggest that single-electron oxidation of benzyl group and an amidyl anion formed in situ with subsequent1,5-HAT would both lead to the formation of benzyl radical.Next,we further explore the applicability of our method in generating pseudo-natural cyclic peptides.We employed proline-containing peptide as the model substrate for reaction optimization,and the synthesis and biological test of diverse cyclic peptidomimetic are underway.Part ?:The Synthesis and Anti-TB Evaluation of Natural Product Inspired Aza-polycyclic CompoundsTuberculosis is a highly infectious disease which caused by mycobacterium tuberculosis.However,the current drug regimen for drug-sensitive tuberculosis is no longer be an effective treatment for drug-resistant tuberculosis.And a longer duration and more complex combination drug regimens for drug-resistant tuberculosis leads to severe adverse drug reactions and poor patient adherence which result in a decreased treatment success rate.With current drug therapies all target Mtb,host-directed therapies(HDT)have gained attention as they provide attractive new opportunities for TB treatment.Mtb infection triggers the upregulation of PPM1A,which blocks both cytokine production and apoptosis of Mtb-infected macrophages by activating PPM1A-JNK pathway,thereby favoring the intracellular survival of Mtb.It suggests that PPM1A is a potential target for TB HDT which would shorten tuberculosis treatment duration,prevent tissue injuries and persistent infection.However,to date,no pharmacological inhibitors of PPM1A exist.Several studies shows that sanguinarine is potently inhibited the phosphatase activity of PPM1A.However,low specificity and high cytotoxicity of sanguinarine severely limit its usefulness as a chemical probe and therapeutic drug.In the fourth chapter of this paper,we designed and synthesized a series of phenanthridium compounds with potent inhibitory activity of PPM1A through the skeleton transition,bioisosteric,and dominant fragment integration strategies.Among them,17-5 and 18-4 exhibit excellent inhibitory activity against PPM1A,reaching an IC₅₀ of 1?M and 2.5?M through p NPP-based enzymatic assay.And 17-5 and 18-4possess greater than 15-fold and 40-fold selectivity,respectively for PPM1A than PPM1B.In addition,the tested bioactive compounds showed no effect on cell viability.What's more,the reduction in intracellular Mtb burden following 18-4 treatment is due to a host-directed effect since 18-4 has no direct effect on Mtb growth in axenic cultures.However,17-5 did not enhance bacterial clearance in infected macrophages.Next,we sought out to test the efficacy of 18-4 in Mtb infected mice.The results show that while single treatments with 18-4 or a low-dose rifampicin are not effective in reducing the Mtb burden in the lungs,but their combination treatment leads to a significant 1-log reduction in bacterial burden.And the absence of a hyper-inflammatory response in vivo after 18-4 treatment reasonably support its safety for HDT and its possibility for preventing tissue injury caused by excessive inflammatory in chronic pulmonary tuberculosis.Collectively,18-4 that we optimized from sanguinarine,is the first available effective,specific,and safe pharmacological inhibitor of PPM1A,which would be utilized as small-molecule chemical probes to investigate fundamental biological mechanisms.