I. A. Tolmacheva

SYNTHESIS OF LUPANE AND 19β,28-EPOXY-18α-OLEANANE 2,3-seco-DERIVATIVES BASED ON BETULIN

The α-hydroxyoximes of methyl betulonate and allobetulone were synthesized. Beckmann fragmentation of them produced the lupane and 19β,28-epoxy-18α-oleanane 2,3-seco-derivatives.

Synthesis and antiviralactivity of 2,3-seco-derivatives of betulonic acid

A lupane 2,3-seco-aldehydoacid that was oxidized further to the 2,3-seco-diacid was synthesized by Beckmann fragmentation of the α-hydroxyoxime of betulonic acid. It was found that both 2,3-seco-derivatives were capable of suppresing reproduction of Herpes type 1 and flu A viruses (EC50 from 1.9 to 21.3 μM).

Triterpenoids with a Five-Membered a-Ring: Distribution in Nature, Transformations, Synthesis, and Biological Activity

The literature on the distribution in nature, structural variations, isolation, identification, and biosynthesis issues of triterpenoids with a five-membered A-ring was reviewed. The principal trends in approaches to the synthesis of structural analogs of such compounds were discussed. Information on the biological activity of natural and semi-synthetic A-pentacyclic triterpenoids was presented.

Antiviral activity of 2,3-secotriterpenic hydrazones of the lupane and 19β,28-epoxy-18α-oleanane types

Novel hydrazones of the lupane and 19β,28-epoxy-18α-oleanane types have been synthesized via the interaction of 2,3-secotriterpenic aldehydonitriles with substituted hydrazines. As a result of the investigation of the antiviral activity of 2,3-secotriterpenic hydrazones against the Indiana strain of the vesicular stomatitis virus on two models of mammalian cell line infection, the acetylhydrazone of 1-cyano-2,3-seco-19β,28-epoxy-18α-olean-3-al has been found to have a high prophylactic activity of 0.00016 μg/ml to the vesicular stomatitis virus and to inhibit virus reproduction in primarily infected cells in a 0.21-μg/ml concentration.

Synthesis of A-Pentacyclic Triterpene α,β-Alkenenitriles

A-seco-triterpenoids with a methylketone group were synthesized from epimeric 3-hydroxy-3-methyl-1-cyano-2,3-seco-triterpenoids of the lupane and 19β,28-epoxy-18αH-oleanane types, which were formed by a Grignard reaction. The resulting methylketones underwent under base-catalysis conditions an intramolecular cyclization to form A-pentacyclic β-substituted alkenenitriles. The synthesized compounds included 3-methyl-1-cyano-19β,28-epoxy-2,3-seco-2-nor-18αH-olean-3-one and methyl 3-methyl-1-cyano-2-norlup-1(3),20(29)-dien-28-oate, which inhibited in vitro reproduction of human immunodeficiency virus type 1.

Synthesis and biological activity of mono- and diamides of 2,3-secotriterpene acids

Amides of four types were synthesized derived from 2,3-seco-18αH-oleanane and 2,3-secolupane mono- and dicarboxylic acids. The spectrum of diamide derivatives was expanded with C3-C3′ and C28-C28′ biscondensed amides with two A-secotriterpene backbones obtained by the interaction of monocarboxylic A-seco acids with lysine. Among the synthesized monoand diamide derivatives, potential inhibitors of herpes simplex virus type 1 replication were found, namely, some compounds with an ethyl β-alaninate fragment (EC50 8.7 and 4.1 μM). The ethyl β-alaninate diamide was shown to combine antiherpetic and anti-HIV activity (EC50 5.1 μM). For the active compounds, the ratios of maximum tolerable concentrations to EC50 ranged from 9.7 to 40.8. The synthesized amides did not show any marked cytotoxic effects against human rabdomiosarcoma RD TE32, A549 lung carcinoma, and melanoma MS cell lines.

The immunotropic activity of lupane and oleanane 2,3-seco-triterpenoids

The immunotropic effect of the 2,3-seco derivatives of allobetulon, betulonic acid, and the methyl ester of betulonic acid were studied. It was found that the highest activity is shown by compounds with an oleanane fragment. The presence of a free C28-carboxyl group enhances the activity of lupane 2,3-seco derivatives. A significant contribution to the development of the immune response is introduced by a functional group at the C3 atom in the A ring—the C3-carboxy derivatives intensify the processes of antibody production and alter the number and ratio of leukocyte forms. It is shown that 2,3-seco-1-cyano-19β,28-epoxy-18α-olean-3-oic acid stimulates humoral immunity with a positive influence on hematopoiesis.

The synthesis of triterpenic amides on the basis of 2,3-seco-1-cyano-19β,28-epoxy-18α-oleane-3-oic acid

Novel 2,3-seco-triterpenic amides were prepared by the interaction of the chloride of 1-cyano-19β,28-epoxy-18α-oleane-3-oic acid with primary amines and synthetic and biogenic amino acids. A cytotoxic triterpenic conjugate with a residue of the ethyl ester of β-alanine was found among the synthesized nitrogen-containing derivatives. Treatment with this conjugate in a concentration of 100 μM resulted in the 45.5% survival of melanoma cells in the medium.

Synthesis of 1-cyano-2,3-seco-derivatives of glycyrrhetic acid

1-Cyano-2,3-seco-derivatives of the 18βH-oleanane series were synthesized from glycyrrhetic acid.

CHEMICAL CONVERSIONS OF BETULONE PRODUCED BY BIOTRANSFORMATION

The possibility of transforming betulone formed by bio-oxidation of betulin by intact R. rhodochrous IEGM 66 cells was studied. The corresponding mono- and diglutaryl derivatives were prepared from betulone and its oxime. Beckmann fragmentation of 28-benzoyloxy-3-hydroxyiminolup-20(29)-ene synthesized 3,4-secolupane derivatives.