Title : A new representative of poly(sugar acids): Acidic polysaccharide poly[3-(3,4-dihydroxyphenyl)glyceric acid], its synthetic analogues and potential therapeutic effect
A new polysaccharide is 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 biopolymer. 3,4-Dihydroxyphenyl and carboxyl groups are regular substituents at two carbon atoms in the chain with the 3-(3,4-dihydroxyphenyl)glyceric acid residue as the repeating unit. PDPGA as a 3,4-dihydroxyphenyl derivative of poly(2,3-glyceric acid ether) belongs to a class of an acidic polysaccharides [poly(sugar acids)] as well. Its basic monomeric moiety glyceric acid is oxidative form of the aldotriose glyceraldehyde. In this case poly(2,3-glyceric acid ether) chain is the backbone of this polymer molecule and 3,4-dihydroxyphenyl groups are regular substituents at 3C carbon atoms in the chain. has not been reported. From the chemical viewpoint, the biosynthesis of the rather rare class of natural polyethers that PDPGA belongs to can be conceived as the epoxidation of the double bond in caffeic acid followed by the polymerization of the resulting oxirane. PDPGA as a unique natural polyether contains aliphatic ether groups in its polymer backbone. Naturally occurring ethers include small molecules such as antibiotics, or aromatic polymer such as lignin. Lignin contains ether links between two aromatic rings or between an aromatic ring and an aliphatic moiety. However, reports concerning polymers that contain aliphatic ethers as repeating unit are missed. Every repeating structural unit of PDPGA contains three reactive functional groups, two phenolic hydroxyl groups in ortho-position and one carboxyl group. The structural unit of synthetic polymers poly(1,2-glyceric acid carbonate) and poly(1,2-glycerol carbonate) contain only one reactive carboxyl and one reactive –CH2OH groups, respectively. Overall, multifunctionality of PDPGA should be a reason of its wide spectrum of biological activities. The basic monomeric moiety of PDPGA was synthesized via Sharpless asymmetric dihydroxylation of trans-caffeic acid derivative using a potassium osmate catalyst. Methylated derivative of PDPGA was synthesized via ring opening polymerization (ROP) of 2-methoxycarbonyl-3-(3,4-dimethoxyphenyl)oxirane using a cationic initiator BF3·OEt2. Oligomers of PDPGA was synthesized by “green” ROP enzymatic polymerization of methyl 3-(3,4-dibenzyloxyphenyl)glycidate using lipase from Candida rugosa. Enzymatically obtained oligomers of natural polyether cause interest for diverse biological tests. 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 exerted anticancer activity in vitro and in vivo against androgen-dependent and -independent human prostate cancer (PCA) cells via targeting androgen receptor, cell cycle arrest and apoptosis without any toxicity, together with a strong decrease in prostate specific antigen level in plasma. The anticancer efficacy of PDPGA against human PCA cells is more compared to its synthetic monomer. Methylated PDPGA did not show any activity against PCA. Thus, PDPGA was identified as a potent agent against PCA without any toxicity.