Victor N. Odinokov

Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo.

We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76 μg/mL) and 11 (IC50 of 0.64 μg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo.

Synthesis of 7,8α-dihydro-14α-deoxyecdysteroids.

A Pd-C-catalyzed hydrogenation in methanol and in the presence of sodium methylate is a simple, convenient and high yielding reduction method to convert the 7,14-dien-6-one ecdysteroids to their corresponding 7,8α-dihydro-14α-deoxyecdysteroids.

Hydrogenation of ecdysteroids.

Catalytic hydrogenation is extensively used in steroid chemistry. The interest in transformations to the steroid skeleton of ecdysteroids has been increasing in the past years. Essential interest in the chemistry of ecdysteroids is caused by the selective reduction of Δ7 bond with the formation of 7,8-dihydro analogues, because this process allows one to obtain modified structures with new biological activity. Catalytic hydrogenation of isolated and conjugated double bonds and functional groups in ecdysteroids derivatives has been considered in review.

Modification of Hyaluronic Acid with Aromatic Amino Acids

Hyaluronic acid was modified with aromatic amino acids (5-aminosalicylic, 4-aminosalicylic, anthranilic, and p-aminobenzoic) in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. The modified glycans contained 9–43% of arylamide groups and 10–33% of isoureidocarbonyl groups depending on the nature of the amino acid. Reduction with sodium borohydride allowed the conversion of isoureidocarbonyl groups into hydroxymethyl groups.

Stereospecific 7α-alkylation of 20-hydroxyecdysone in a lithium-ammonia solution.

The reaction of 20-hydroxyecdysone with methyl or ethyl iodide or allyl bromide in a lithium-ammonia solution results in stereospecific 7α-alkylation to give 7α-methyl-, 7α-ethyl-, and 7α-allyl-14-deoxy-Δ(8(14))-20-hydroxyecdysones, respectively. By catalytic hydrogenation (Pd-C/MeOH), the 7α-allyl derivative was converted to 7α-n-propyl-14-deoxy-Δ(8(14))-20-hydroxyecdysone.

Hydroxylation and epimerization of ecdysteroids in alkaline media: Stereoselective synthesis of 9α-hydroxy-5α-ecdysteroids

Autoxidation of diacetonides of 20-hydroxyecdysone and ponasterone A under treatment with excess of NaOH in methanol leads to the formation of 9α-hydroxy-5α-ecdysteroids previously not described. Their structures have been determined by detailed NMR analysis. Catalytic hydrogenation (Pd-C, MeOH-MeONa) of hydroxylated ecdysteroids affords the 7,8α-dihydro-9α-hydroxy-5α-ecdysteroids.

The in vitro resistance of oxidized hyaluronic acid to testicular hyaluronidase.

Hyaluronic acid belongs to the class of acid glycosaminoglycans, heteropolysaccharides with a linear structure. This is the key compound of the extracellular matrix that performs important functions in the organism. It is composed of repeated units represented by glucuronic acid and N -acetylD -glucosamine. The interest to the derivatives of hyaluronic acid displaying a decreased enzymatic biodegradability has increased recently due to their potential as controlled release drugs [1–3]. We have found that the oxidation of hydroxymethyl groups into carboxyl groups renders hyaluronic acid resistant to testicular hyaluronidase in vitro. Hyaluronic acid ( I ) was obtained by alkaline extraction from the umbilical cord of newborns and purified by anion exchange chromatography on DEAE cellulose as described in [4]. Modified hyaluronic acid II was obtained by treating hyaluronic acid I with sodium hypochlorite in the presence of sodium bromide and a catalytic amount of 2,2,6,6-tetramethylpiperidine-1oxyl (TEMPO) in water [5]:

Chemical modification of heparin

Heparin was modified at carboxyl groups by reaction with several pharmacologically important amino-containing compounds in aqueous medium in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. In dependence on the nature of the amine and the ratio of reagents, conjugates containing 36–100% amide and 0–25% isoureidocarbonyl groups were synthesized. Isoureidoarylamide groups are present, along with amide moieties, in the products of heparin modification by hydroxyl-containing aromatic amines. The conjugate of heparin with p-aminobenzoic acid contained oligomeric arylamide.

7α-Alkylation and 7,7-bis-alkylation of 20-hydroxyecdysone with propargyl bromide in a lithium–ammonia solution and catalytic reductive spirocyclization of 7,7-bis(2-propyn-1-yl)-14-deoxy-Δ8(14)-20-hydroxyecdysone

7α-Alkylation and 7,7-bis-alkylation of 20-hydroxyecdysone with propargyl bromide in a lithium-ammonia solution resulted in the formation of 7α-(2-propyn-1-yl)- and 7,7-bis(2-propyn-1-yl)-14-deoxy-Δ(8(14))-20-hydroxyecdysone in 92% and 75% yield respectively. Upon catalytic hydrogenation (10% Pd-C) of 7,7-bis(2-propyn-1-yl) derivative spirocyclization occurs by geminal 2-propyn-1-yl groups.

Convenient one-pot synthesis of resin acid Mannich bases as novel anticancer and antifungal agents

AbstractThe one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl esters by formaldehyde and secondary amines was studied for the first time. The novel diethylamino, pyrrolidine, and morpholine-substituted butynyl derivatives of abietic, dehydroabietic, levopimaric, maleopimaric and dihydroquinopimaric acids were obtained. It was shown that synthesis of the abietic acid propargyl ester by the reaction of the abietane diterpenoid with oxalyl chloride and dimethylformamide is accompanied by the formylation of the ring B at the C-7 position and the dehydrogenation of the ring C to form the dehydroabietic acid ester. The cytotoxic, antibacterial and fungicidal activities of the synthesized compounds were studied in vitro. The experimental results showed that the most promising compound was 7-formyl abietic derivative Mannich base with a pyrrolidine substituent, with an MIC of 16 μg/ml against methicillin-resistant S. aureus ATCC 43300, and 8 μg/ml against C. albicans ATCC 90028 and 4 μg/ml against C. neoformans H99; ATCC 208821. The dihydroquinopimaric acid derivative with the diethylamine fragment showed the greatest antiproliferative activity towards twelve tumor cell lines.