Title: Poly(gyceric acid ether): A new 3,4-dihydroxyphenyl derivative of polysaccharide from medicinal plants, its synthetic analogues and their comparative anticancer efficacy

Abstract

The main chemical constituent of high molecular (>1000 kDa) water-soluble preparations from medicinal plants of Symphytum asperum, S.caucasicum, S.officinale, S.grandiflorum, Anchusa italica, Cynoglossum officinale and Borago officinalis (Boraginaceae) according to data of liquid state 1H, 13C NMR, 2D 1H/13C HSQC, 2D DOSY and solid-state 13C NMR spectra was found to be poly[oxy-1-carboxy-2-(3,4- dihydroxyphenyl)ethylene] or poly[3-(3,4- dihydroxyphenyl)glyceric acid] (PDPGA). The polyoxyethylene chain is the backbone of this regular polymer with the repeating unit 3-(3,4-dihydroxyphenyl)glyceric acid residue. PDPGA as a 3,4-dihydroxyphenyl derivative of poly(glyceric acid ether) belongs to a novel class of acidic polysaccharides (sugar acids) as well. Its basic monomeric moiety glyceric acid is a natural three-carbon sugar acid which is oxidative form of aldotriose glyceraldehyde. The monomer of PDPGA 3-(3,4-dihydroxyphenyl) glyceric acid was synthesized via Sharpless asymmetric dihydroxylation of trans-caffeic acid using a potassium osmate catalyst which is new findings in sugar acids. Methylated derivative of PDPGA was synthesized via ring opening polymerization of 2-methoxycarbonyl-3-(3,4- dimethoxyphenyl)oxirane using a cationic initiator (BF3•OEt2). Human Hyaluronidase (Hyal-1) degrades high molecular mass Hyaluronic acid (HA) into smaller fragments which have pro-inflammatory effects. PDPGA possesses the ability to inhibit the enzymatic activity of Hyal-1 completely. Consequently PDPGA exhibited anti-inflammatory efficacy. PDPGA and its synthetic monomer suppressed the growth and induced death in androgen dependent (LNCaP) and -independent (22Rv1) human prostate cancer (PCA) cells. PDPGA induced apoptotic death by activating caspases, and also strongly decreased androgen receptor and prostate specific antigen (PSA) expression. In 22Rv1 xenograft model male athymic nude mice with 22Rv1 xenografts was administered orally of PDPGA. Plasma analyses revealed that PDPGA administration caused a strong dose dependent decrease in PSA levels by 87%. Anticancer efficacy of PDPGA against PCA cells is more compared to its synthetic monomer. Methylated PDPGA did not show any activity against PCA. Overall, this study identifies PDPGA as a potent agent against PCA without any toxicity.