Design, Synthesis, Stereoselective And Biological Studies Of1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-Glucopyranose Analogues

Cancer remains a devastating disease and the number of cancer related deaths isincreasing, though the rapid advances in diagnostic and operative techniques have beenintroduced, cancer remains a most difficult human malignancy to treat. Including all othercancers the lung and colon cancers are the second and third common malignancy inhuman beings and a leading cause for deaths. More and more researchers are engaged inthe cancer treatment studies all around the world in various fields including the designingand developing the new, potent, effective drugs with minimal side effects.Polyphenols which can be defined as, Water soluble phenolic compounds havingmolecular weights between500and3000(Da) and besides giving the usual phenolicreactions, they have special properties such as the ability to precipitate alkaloids, gelatinand other proteins from solution. Polyphenols are the plant secondary metaboliteswidely distributed in different sectors of higher plant kingdom. Studies showed thatpolyphenols are effective in the inhibiting of lots of cancers, including Lung Cancer,Breast Cancer, Gastric Carcinoma, Colonic Cancer, Leukemia, Melanoma，and ProstateCancer and so on. It is reported that polyphenols has low toxicity, definitely curativeeffect, and multiple target therapy characteristic, which make it to be an attractive topic inMedicinal Chemistry and Pharmacology.Oxidants are the by-product of normal metabolism which causes extensive damage toDNA, proteins and lipids. And this damage considered as a major contributor to the agingand degenerative disease, such as cancer, cardiovascular disease, immune-system declineand others. Enhanced ROS levels are involved in tumor initiation and promotion and mayultimately lead to carcinogenesis. Hence, the free radical and scavenging properties ofpolyphenols make them a class of interest for the designing new anti-tumor drugs.In the present work, we employed the1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-α,β-D-glucopyranose (PGG) as our leading compound and synthesized its various analogues in order to study the structure activity relationship. Lung and colon cancer celllines were selected for the biological assays, and also Influenza A virus inhibition studiesperformed for selective compound.In the present work, we have synthesized the two main series of PGG analogues withdifferent aromatic ring substitutions in Galloyl moiety. Series1include the methoxy,benzyloxy and free hydroxyl analogous of PGG with different benzoyl groups; series2include the methoxy, benzyloxy and free hydroxyl analogous of PGG with differentcinnamoyl groups.2-D-glucosamine derivative of pentagalloyl D-glucose (PGG) wasalso synthesized in order to study the effect of amide at2-position in glucose core intumor inhibition. Methoxylated derivatives of PGG are also synthesized with D-mannosesugar core to analyze the screening of anti-viral activity. In total,42targeted compoundswere synthesized from which23were new. Known synthetic methods were used forsynthesis of targeted compounds and all compounds were characterized by NMR (1HNMR,13C NMR) and HRMS. For some compounds the alpha and beta anomers wereseparated on normal silica gel column with common solvents as eluent.Anomeric selectivity studies for galloylation also studied in this paper. Resultsdemonstrate that, base catalyst (DMAP) favors the selectivity for-isomer, while acidand carbodiimide favor the selectivity for β-isomer when stoichometric amounts wereused. Sterric inference between,β-unsaturated acid and C-2OH stereochemistry(adjacent carbon to anomeric) in sugar effect the anomeric selectivity with both D-glucose and D-mannose. The coupling reagent EDC favors the selectivity for beta isomerin the reactions of benzoic acid with sugars.The synthesized compounds were screened against the four tumor cell lines, whichinclude the two lung cancer (A549and H1299) and two colon cancer (HCT116andHT29). The primary screening of two series of compounds1-6,8-11,17-23and39-42with protected/methoxy groups was analyzed at concentration of100μM while the9compounds with Hydroxyl PGG were screened for their IC50analysis with abovementioned positive controls. The compound4with a methoxy group at p-position inaromatic ring find to be more potent in series1; it shows less cell viability about72%which is in turn more effective than control GA which shows cell viability near90% against A549. The compounds8-11with benzyl group are appeared inactive. The series2compounds17-23in primary screening with a side chain double bond and one or twomethoxy/benzyloxy substituients on aromatic ring appeared inactive against all screenedcell lines.IC50values against cell lines show that the inhibition efficacy of compound12(1,2,3,4,6-Pentakis[-O-(3,4,5-trihydroxybenzoyl)]-,β-D-glucopyranose (PGG) appear to be moreeffective than other compounds (including series2) against HCT116and A549cell lineswith IC50of1.61μM and3.02μM while the compound161,2,3,4,6-Pentakis[-O-(4-hydroxy,3-methoxy benzoyl)]-,β-D-glucopyranose (PVG) appear more effective thanPGG and all compounds against HT29and H1299cell lines with IC50of1.76μM and3.65μM. Both compounds12and16in addition with compound27(series2) appearmore effective than control doxorubicine (IC50=6.70) against H1299with IC50s of3.84μM,3.65μM and6.31μM respectively.Substitutions on aromatic ring and side chain double bond have dominant effect on cellinhibition.Increasing OH substitution enhance the activity, this works well withcompounds in series1. Compound13more potent than compound14against HCT116and A549with IC50values of7.46μM and7.89μM respectively. Compound15, whichis o-substituted; show no activity due intramolecular H-bond which hinders theavailability of free OH group. Components in series2appear not good effective exceptcompound27p-hydroxy with a2-C side schain almost show the same efficiency tocompound12and13against HT29and HCT116/A549cell lines with IC50of4.55μM,6.03μM and7.44μM respectively. While the compounds with dihydroxy substitutionshow not effective results.Anti-influenza A virus activities of selective methoxylated analogues were tested and the-anomer showed higher activity than β-anomer. The compound17-αβ with IC50value of66.5μM appears twofold more potent than Ribavirin (an anti-viral drug) which has IC50value113.1μM. The cinnamic acid analogues appear more potent than benzoic acidanalogues, which show that the side chain double bond could be major pharmacophorefor viral inhibition. In the present paper, we are first time reporting the cinnamic acid and methoxylatedanalogues of PGG along with glucosamine derivatives. SAR of the PGG analoguesagainst tumor cell line inhibition and Influenza A virus screening are also first timereporting. we are demonstrate, the presenting work could be helpful, applicable and abase for the designing and developing more lung and colon cancer targets. And also apreliminary data source for targeting and molecular biology studies, in addition also forthe epidemiological studies of PGG analogues.