New cyclopropane derivatives of betulin were synthesized by attachment of dichlorocarbenes or dibromocarbenes to the double bond of betulin diacetate, followed by the deprotection of hydroxyl groups. The betulin cyclopropane derivative was obtained from 20,29-dihydro-20,29-dichloromethylenebetulin by treatment with lithium in tert-butanol. These compounds were converted into the corresponding derivatives of betulonic acid by oxidation with chromium trioxide. The reduction of oxo group with sodium borohydride led to the corresponding derivatives of betulinic acid. 20,29-Dihydro-20,29-dichloromethylenebetulinic acid proved to be the most cytotoxic toward human melanoma of the Colo 38 and Bro lines and human ovarian carcinoma of the CaOv line (IC50 10 microM). 20,29-Dihydro-20,29-dibromomethylenebetulinic acid inhibited the growth of the Bro melanoma cell line and the CaOv carcinoma cell line practically by 50% at a concentration of 10 microM. The other derivatives of betulinic and betulonic acids were active toward all of the three cancer cell lines at concentrations higher than 10 microM. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.

Previously unknown amino-derivatives of the natural sesquiterpene lactone α-santonin were synthesized. The activity of the products against several human tumor-cell lines was studied.Natural sesquiterpene lactones exhibit various types of biological activity including antitumor activity [1]. A study of structure-activity relationships has found that high cytotoxicity correlates with the presence of an exocyclic double bond in the lactone ring [2]. Furthermore, the presence of an activated double bond allows modification (by a Michael reaction), introduction of new pharmacophores, and production of water-soluble and transportable forms [3].Compounds containing in a lactone ring not a methylene group but a methyl are found among the large variety of natural sesquiterpene γ-lactones isolated from plants of the family Asteraceae. For example, austricin (1) [4] was isolated from Artemisia leucodes Schrenk, A. austriaca Jacg.; arborescin (2) [5], from A. arborescens L.; and balchanolide (3) [6], from Achillea millefolium L. and A. balchanorum H. Krasch, etc.These and other sesquiterpene lactones with a methyl in the lactone ring are found in plants in large quantities and can be considered promising synthons for modification in order to introduce a new reactive center such as an activated exocyclic double bond that reacts readily with nuclophiles. These transformations could produce new derivatives of natural sesquiterpene lactones containing pharmacophores and their water-soluble or transportable forms.Our goal was to use α-santonin (4), which is isolated from certain Artemisia species (Asteracea), as an example to demonstrate the ability to introduce an active methylene into the lactone ring, to use the resulting lactone as a synthon for synthesis of previously unknown amino-derivatives of lactones, and to study their cytotoxic activity.Chemical and biochemical transformations of α-santonin and its pharmacological properties have been studied already for over 100 years. It has been used previously as an antiparasite preparation [7]. Other types of activity have recently been found for it, for example, antipyretic, anti-inflammatory, and fungicidal [8,9]. Santonin presents several reactive centers and is a convenient starting material for further chemical modification. Various transformations involving the dienone ring have been reported [10][11][12][13]. Methods for opening the lactone ring using various reagents are known [1,14,15].

Objective: to evaluate the prospects of the glycosides of indolocarbazole containing amino acid residues as potential antitumor compounds. Materials and methods. For 32 compounds by structural formulas using the methods of chemoinformatics, a number of molecular descriptors and the probability of manifestation of various types of biological activity were calculated, the cytotoxic activity was evaluated in vitro by methylthiazole tetrazolium (MTT) assay using five human tumor cell lines. Results. For the studied amino acid derivatives of glycosides of indolocarbazole, a high probability of antitumor activity with a low probability of cytotoxic activity in vitro is predicted by computer method. Low cytotoxic activity was confirmed in the MTT test on 5 cell lines. Computer methods were used to predict the mechanisms of possible antitumor activity and to calculate a number of molecular descriptors that are important for the qualification of substances as potential drugs. Conclusion. It is expedient to study the antitumor activity of amino-acid derivatives of glycosides of indolocarbazole in experiments on animals with transplanted tumors.

Background. Some natural carotenoids have anti-carcinogenic, anti-mutagenic, and immunomodifying activity and may be considered as potential agents for chemoprevention of cancer. Objective: to study pharmacokinetics of beta-carotene, cantaxantene, lycopene, and carotene-containing compounds created on the base of the mentioned substances. Materials and methods. The study used carotene-containing drugs, which we previously created, such as Betask, Kaskatol, Tomatol, natural carotene-tocopherol complex derived from cankerberry. The research was conducted on mice, rats, rabbits, dogs, piglets, monkeys (Javanese macaque); the observations also involved healthy donors and patients with colorectal cancer before surgery. Carotenoid and retinoid detection was made by high performance liquid chromatography in blood plasma and liver tissue. Results. Comparative analysis of pharmacokinetics of the studied carotenoids demonstrates their relatively low absorption in animals. Bioavailability varies significantly among species; and it increases in the following order: dogs, rabbits, mice, rat, piglets, humans. Pharmacokinetics of carotenoids and carotene-containing compounds was studied with single and multiple administration per os. Cantaxantene and lycopene have a better bioavailability as compared to synthetic beta-carotene. Pharmacokinetics of synthetic carotenes and carotenoids of carotene-containing compounds has no significant differences. Beta-carotene in natural carotene-tocopherol complex has higher bioavailability (2-4 fold higher) as compared to synthetic beta-carotene. Regular complex administration into monkeys results in enhanced beta-carotene levels in blood serum of the animals and inhibits chemically induced carcinogenesis. The patients’ intake of beta-carotene in the pre-operational period was associated with the enhanced pro-vitamin levels in blood serum and stimulation of a number of cellular immune parameters. Conclusions. The studied carotenoids and carotene-containing compounds may be used in combined antitumor therapy and as treatment and prophylactics agents in cancer risk groups.

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