V. P. Fedotov

Steroid nitrates. II. Synthesis and hormonal activity of 9α,11β-dihydroxyestra-1,3,5(10)-triene 11-nitrates

Abstract11-Nitrates of 9α,11β-dihydroxy derivatives of estrone, estradiol, and ethinylestradiol were synthesized by oxidative nitration of the corresponding estratriene 3-acetates with cerium ammonium nitrate. Three methods are given for this reaction. Compounds had high antifertility and estrogen activity. Antifertility actions were much greater than their estrogen activities, as compared with the similar levels seen with ethinylestradiol.

Synthesis and biological activity of C8-ISO and D-homo analogs of estrone oxidized in ring B

I. L. Kh. Kostenko and E. G. Rozantsev, Biokhimiya, 48, No. 9, 1437-1440 (1983). 2. M. S. Kushakovskii, Clinical Forms of Hemoglobin Damage [in Russian], Leningrad (1968), pp. 37-41. 3. A. E. Lutskii, N. A. Krivleva, and E. M. Obukhova, Zh. Obshch. Khim., 45, 432-438 (1975). 4. M. D. Mashkovskii, Medicinal Agents, 8th edno, Moscow (1977), Vol. I, pp. 176-177. 5. L. Gopal, C. I. Jose, and A. B. Biswas, Spectrochim. Acta., 23A, No. 3, 513-518 (1967). 6. N. C. Gujrathi and C. Jose, Indian J. Chem., ~, No. 8, 822~823 (1971). 7. J. Hermans, Jr., S. J. Leach, and H. A. Sceraga, J. Am. Chem. Soc., 85, No. i0, 1390-1395 (1963). 8. W. D. Kumler, J. Org. Chem., 9, No. 8, 822-823 (1971). 9. H. A. Lloyd, K. S. Warren, and H. M. Fales, J. Am. Chem. Soc., 88, No. 23, 5544-5549 (1966). N. Mori, Y. Asano, T. Irie, and Y. Tsuzuki, Bull. Chem. Soc. Jpn., 42, No. 2, 482-487 (1969). F. Rabiner, J. Exp. Med., 12_66, No. i, 1127-1142 (1967). i0.

Insulin secretion-stimulating activity of certain derivatives of the C-terminal tetrapeptide of cholecystokinin

The tetrapeptide amide, possessing amino acid sequence H-Trp-Met-Asp-Phe-Nh 2 (I, CCK-4, trimafam) is a C-terminal structural fragment of gastrin, secretin, and cholecystokinin, and, as we discovered previously [2], has a pronounced stimulating effect on the secretion of insulin, glucagon, and somatostatin. According to the data of [5], the insulin-stimulating effect of tetrapeptide I is substantially more pronounced than that of other larger fragments of cholecystokinin. These investigations open up theoretically new possibilities in the treatment of diabetes mellitus using previously unknown oligopeptide compounds that activate insulin secretion in the pancreas.

Preparation and properties of phenylalanine-B30-(human insulin)

In a directed experimental evaluation of the influence of the replacement of an aliphatic amino acid residue in the C-terminal part of the B-chain of insulin by an aromatic amino acid residue, we have prepared the previously unknown phenylalanine-BS°-(human insulin) and have investigated the biological activity of this analog, which differs from the natural hormone by the replacement of a L-threonine residue by a L-phenylalanine residue.

BIOLOGICAL ACTIVITY OF ESTROGENS OXIDIZED IN THE C RING

Estrogens oxidized in the C ring are the subject of intensive study in connection with the fact that the introduction of an llB-methoxy group sharply enhances their estrogen action Thus, llS-methoxy-17~-ethynylestradiol (brand name Moxestrol) is more effective than all the known estrogens, and, which is especially important, is is taken orally [5]. Moreover, a change in the configuration of the ll-methoxy group leads to the manifestation of antiestrogen properties for the ll=-isomer, which has no analogy in the series of estrogens [i0].

Preparation and properties of a cysteine analog of human insulin

characteristic absorption spectrum in the visible region with a maximum at 470 nm also permitted it to be identified as lactoferrin. Since transferrin, which is present in milk in definite amounts, possesses similar properties we made a qualitative analysis of the N-terminal amino acid. In the protein analyzed this was glycine, which is characteristic for lactoferrin, and not valine, which is characteristic for transferrin.

Preparation and properties of the methyl ester of\(Willardine^{B_{3 0} }\)-(human insulin)

To study the molecular mechanisms of the interaction of human insulin with the receptors, it is necessary to have available structural analogs of this hormone that retain a high biological activity and are readily detectable in complex mixtures by methods of nondestructive analysis. One such method is spectrometry in the near ultraviolet region. However, human insulin and related animal insulins possess extremely limited UV absorption because of the presence in the A and B chains of insulin of residues of the aromatic protein amino acids tyrosine and phenylalanine, which are relatively weak chromophores.

Preparation and properties of a new structural analog of human insulin — AsparagineB30-insulin

The trypsin-catalyzed transamination [i] of porcine insulin (II) takes place on the reaction of the latter with the tert-butyl ester of L-asparagine (III) in an aqueous organic med• . • o r lum (water--dlmethylformamlde) at 24 C and pH 6.3. Unde these conditions, the tryptic transamination reaction proceeded only at the Lys D29 residue, and the undesirable side reaction of the Arg B22 residue did not occur.

Preparation and properties of leucine-B30-insulin

The hydrolysate was separated on a column (i.i × 70 cm) of Sephadex G-50 fine equilibrated with 30% CH3COOH. As in the case of cyanogen bromide cleavage a peptide of low molecular mass was obtained for which the N-terminal amino acid was found to be Val and the amino acid composition: Vall, Asps, Serl, Glu3, Glyl, Alsl, Leul, Phel, Argl. The yield of peptide was 15%. The compositions of the peptides were determined after hydrolysis in 5.7 N HCI at II0°C for 24 h on a LKB 4101 analyser.

Silylsteroids. IV. Hormonal activity and physicochemical properties of C-trimethylsilylestrogens

This communication is a continuation of our investigations [I]. The high hormonal activity observed in many silyl ethers of hydroxysteroids [2-5] has drawn attention to siliconcontaining steroids as a potential source of new hormonal drugs [6]. The activity of silyl ethers of hydroxysteroids by oral administration, and the increased duration of their effect, is due to the lipophilicity of these compounds and their hydrolytic conversion in the body into active steroids. The properties of silicon-containing steroids of a nonether type have scarcely been investigated [7, 8]. In view of the lability of the bond between silicon and the aromatic ring in arylsilanes [9], silylestrogens would be expected to regenerate the parent estrogen in the body, and there should be a connection between the ability to undergo such regeneration and the magnitude of the estrogenic effect.