Pharmacological activities of natural triterpenoids and their therapeutic implications

Pharmacological properties of the ubiquitous natural product betulin.

Birch bark research and development

Biocatalytic Selective Modifications of Conventional Nucleosides, Carbocyclic Nucleosides, and C-Nucleosides

Aminopeptidase N (APN)/CD13 (EC 3.4.11.2) is a transmembrane protease present in a wide variety of human tissues and cell types (endothelial, epithelial, fibroblast, leukocyte). APN/CD13 expression is dysregulated in inflammatory diseases and in cancers (solid and hematologic tumors). APN/CD13 serves as a receptor for coronaviruses. Natural and synthetic inhibitors of APN activity have been characterized. These inhibitors have revealed that APN is able to modulate bioactive peptide responses (pain management, vasopressin release) and to influence immune functions and major biological events (cell proliferation, secretion, invasion, angiogenesis). Therefore, inhibition of APN/CD13 may lead to the development of anti-cancer and anti-inflammatory drugs. This review provides an update on the biological and pharmacological profiles of known natural and synthetic APN inhibitors. Current status on their potential use as therapeutic agents is discussed with regard to toxicity and specificity.

/pdf/aminopeptidase-n-cd13-ec-3-4-11-2-inhibitors-chemistry-1civzk5vty.pdf

Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects.

Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses.

Lupane triterpenes and derivatives with antiviral activity.

3 -Hydroxy-lup-20(29)-en-(28)-oic (betulinic) acid (I) was isolated at the beginning of the 20th century and originally called gratiolone [1]. In the past decade, some special biological properties of this triterpenoid has drawn the attention of researchers. In 1994, betulinic acid was found to exhibit anti-HIV-1 activity in H9 lymphocyte cell culture [2]. The most promising inhibitor of HIV-1 replication is 3-O-(3 ,3 -dimethylsuccinate) of betulinic acid [3]. In 1995, it was established that betulinic acid is capable of selectively inhibiting the growth of malignant human melanoma [4]. In addition, betulinic acid and its derivatives possess antibacterial, antimalarial, antiinflammatory, bile-expelling, and other properties [5 – 7]. Since the content of betulinic acid in plants is very low, isolation of this compound from raw plant material is poorly profitable. A more effective method of obtaining betulinic acid is synthesis from betulin (II) and betulonic acid (III). The first synthesis of betulinic acid was suggested by Ruzicka et al. [8]. This original procedure involved (i) protection of the hydroxy groups of II by acetylation, (ii) selective hydrolysis of the acetyl group at C-28, (iii) oxidation of the oxymethyl group to carboxy group, and (iv) removal of the protective acetyl group at C-3. The total yield of betulinic acid from this process did not exceed 30%. In the late 1990s, betulinic acid was synthesized (I) in two steps by oxidizing betulin (II) with Jones reagent or chromic anhydride in acetic acid, followed by selective oxidation of the resulting betulonic acid (III) with NaBH4 [9, 10], whereby the total yield of the target compound reached up to 60%. We used Jones reagent to oxidize the extract obtained by treating birch bark with aqueous isopropanol in an autoclave at 80°C. The initial extract contained up to 90% of betulin and about 5% of lupeol (IV). Betulonic acid (III) formed as a result of this oxidation process was isolated from the reaction mixture in the form of a potassium salt (V) with a yield of 82%, which allowed us to exclude the stage of intermediate product purification by column chromatography [10]. Upon acidification of an ethanol solution of the potassium salt V with a 5% hydrochloric acid solution, betulonic acid (III) of 95% purity was isolated with a yield of 85%. The physicochemical parameters of the product corresponded to the published data [2, 10, 11]. The total yield of betulonic acid (III) calculated for the initial betulin extract was 67%. Column chromatography of the organic fraction yielded 3-keto-lupeol (VI) with a yield of 1.7%.

Synthesis of Betulinic Acid from Betulin Extract and Study of the Antiviral and Antiulcer Activity of Some Related Terpenoids

Betulonic acid amides with aliphatic and heterocyclic amines and with L-amino acids were synthesized by the acid chloride method. Betulonic acid amide and L-methionine derivatives of betulonic acid and its 3-oxime effectively inhibit the influenza A virus. Betulonic acid octadecylamide is active against the herpes simplex Type 1 virus. The conjugate of betulonic acid 3-oxime with L-methionine is also active toward HIV-1. The tested compounds mainly show no activity toward the ECHO6 virus, which is devoid of a coat.

Synthesis and antiviral activity of amides and conjugates of betulonic acid with amino acids

It was reported that derivatives of lupane triterpenoids (lupeol, betulin, betulinic acid) exhibit antiviral activity, in particular, with respect to human immunodeficiency virus (HIV) [1], herpes simplex virus (HSV), and Epstein – Barr virus (EBV) [2 – 7]. Previously, we have also studied the anti-HIV properties of betulin 3,28-di-O-nicotinate [8] and the antiviral activity of some betulin oximes [9] and 28-oxo-allobetulone [10]. In continuation of our investigations of the structure – antiviral activity relationship in the series of lupane triterpenoids, we have synthesized a series of new derivatives and studied their activity in comparison to that of the known compounds. Lupeol 3-O-nicotinate (II) was obtained with 94% yield by acylating lupeol (I) with nicotinic acid chloroanhydride in a mixture of anhydrous pyridine and tributylamine. 2-Furfurylidene methylbetulonate (IV) was synthesized via interaction of methylbetulonate (III) with furfurol in an alcohol solution of alkali (after purification by column chromatography, the product yield was 80%). The proposed structures of compounds II and IV were confirmed by NMR data (see experimental part below). N-formylamine (V) was obtained with a 62% yield using the Leuckart reaction between methylbetulonate (III) and formamide in formic acid. The C NMR spectrum of this compound displays a shift of the signal from the C3 nuclei toward stronger field ( = 56.3 ppm) and reveals a signal due to C1 atom at = 164.1 ppm. In the H NMR spectra, the signals from ptotons of the formyl group is manifested by a singlet at = 8.15 ppm and the NH proton, by a broad signal at = 8.00 ppm.

N. I. Pavlova

Papers

Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses.

Lupane triterpenes and derivatives with antiviral activity.

Synthesis of Betulinic Acid from Betulin Extract and Study of the Antiviral and Antiulcer Activity of Some Related Terpenoids

Synthesis and antiviral activity of amides and conjugates of betulonic acid with amino acids

Synthesis and Antiviral Activity of Lupane Triterpenoids and Their Derivatives