Design, Synthesis And Structure Optimization Of Marine Polypeptide Of Cathepsin D Inhibitor

Cathepsin D(Cath D)is overexpressed and secreted in a number of solid tumors and involved in the progress of tumor invasion,proliferation,metastasis and apoptosis.Inhibition of Cath D is regarded as an attractive pathway for the development of novel anti-cancer drugs.Our previous studies revealed that tasiamide B and designed a hybrid molecule(TB-13)that combine the features of tasiamide B and an isophthalic acid moiety-containing sulfonamide.This compound not only showed high potent activity against BACE1,but also exhibited enhanced selectivity of Cath D over Cath E(6.2-fold)and BACE1(9.8-fold).In order to get a deeper understanding of the SAR,eight analogues of tasiamide were synthesized,including B series 2,C series 4 and D series 2,using [1+2+4]?[2+1+1]?[1+3]?[1+1+4]?[2+1+4] strategy.In this paper,according to the structural characteristics of Tasiamide: containing much polyester structure,N-methylated D-configuration phenylalanine and the activity of the required statin residues designed to synthesize the compound XH-A1.The protected Ahppa was prepared with satisfactory yield and enantioselectivity in four steps from several commercial amino acids.The dipeptide fragment block1 and the tripeptide fragment block2 were prepared by the stepwise extension method.In the end,we completed the synthesis in 12.4% yield.All the fragments were prepared in presence of condensing agents EDC or HATU and HOAt.Afterwards,the protective groups were removed,and the objective analogues were prepared by coupling these fragments using standard solution-phase techniques.We envisioned that the molecular be assembled via amidation between the Leu-Ahppa and Gln-Val because of low hinderance and racemization during fragment coupling.Refer to TB-13 mature synthetic route,toanalogues of tasiamide was synthesized using stepwise by the N-terminal and C-terminal transformation.elongationcompounds were prioritized and submitted to biological assays.The IC50 of the B-class compounds was 665.05 nM and 408.35 nM;the IC50 of the active C-class compounds was 15.01 nM and 353 nM,respectively;the D-class compounds of the basic no inactivity.Notably,compound XH-C2 showed extremely selectivity for CathD with 576-fold over Cath E and 554-fold over BACE1,which could be a valuable template for the design of high potent and selective Cath D inhibitors.Additionally,compound XH-C2 showed moderated activity against HeLa cell lines with IC50 of41.8 ?M.In summary,we have designed,synthesized and evaluated eight tasiamide B derivatives as Cath D inhibitors,in which the core Ahppa unit was retained,B-type compounds gradually reduce the amino acid residues at the N-terminus,but the activity is generally;D-type compounds in the N-terminal introduction of isophthalic acid fragments and transformation,however,poor activity;C-type compounds isophthalic acid fragment was introduced at the N-terminus,while Ala-Me-DPhe-Pro tripeptide at C-terminus was replaced by isobutyl amine,cyclopropyl amine,and3-methoxybenzyl amine,respectively.Enzymatic assays revealed that all these three newly obtained compounds showed moderate to good inhibition against Cath D.Among them,compound XH-C2 exhibited high potent against Cath D(IC50 15 nM)and satisfactory selectivity over Cath E(576-fold)and BACE1(554-fold),which provides a new and good template for the development of selective Cath D inhibitors.