Versatile intermediates in the selective modification of the amino function of 2-amino-2-deoxy-D-mannopyranose and the 3-position of 2-acetamido-2-deoxy-D-mannose: potential membrane modifiers in neoplastic control.

A general method has been developed to selectively modify the amino group of 2-amino-2-deoxy-D-mannopyranose (D-mannosamine), a precursor of the terminal membrane sugar, sialic acid. 1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-alpha-D-mannopyranose oxalate was prepared via two routes that allowed introduction of various acyl groups onto the amino function. These compounds were evaluated for their antineoplastic properties. The most significant preclinical therapeutic finding was the antileukemic activity found in mice for tetra-O-acetyl-2-epi-streptozotocin (the acetylated alpha-mannosamine epimer of streptozotocin). Administration of 50 mg/kg/day x 5 to leukemia L1210-bearing DBA/2Ha mice resulted in 5/5 35-day survivors. Neutralization of 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-alpha-D-mannopyranose oxalate under aqueous conditions led to 2-acetamido-1,4,6-tri-O-acetyl-2-deoxy-alpha-D-mannopyranose, the oxidation of which gave 2-acetamido-4,6-di-O-acetyl-1,5-anhydro-2-deoxy-D-erythro-hex-1-en-3- ulose. This agent demonstrated an IC50(2) of 25 microM with a murine L1210 cell culture. Administration of 100 mg/kg/day x 5 resulted in 42% ILS3 in DBA/2 mice with ip L1210 leukemia. Several other nonacetylated derivatives were also prepared by direct N-acylation, producing, for example, fluorescently tagged N-dansylmannosamine.

Modified steroid hormones. 7. 4-Fluoro-17 beta-estradiol: carbon-13 nuclear magnetic resonance, crystal and molecular structure, and biological activity.

The 4-fluoro analogue of 17 beta-estradiol was investigated for estrogenic action in rats by determination of uterine hyperemia and [3H]uridine incorporation and was found to be an active estrogen. Antitumor activity of this analogue was demonstrated against 7,12-dimethylbenz[a]anthracene (DMBA) induced rat mammary adenocarcinoma. Its 13C NMR spectrum was determined, and all signals were assigned. A detailed X-ray diffraction investigation of 4-fluoro-17 beta-estradiol was carried out, and it crystallized in triclinic space group P1 with two steroids and one methanol in a unit cell of a = 7.367 (1), b = 9.363 (6), c = 12.531 (1) A, alpha = 89.31 (3), beta = 93.38 (1), gamma = 109.62 (3) degrees, V = 812.8 A3, and Z = 2. The structure was solved and refined to an R index of 0.062 using 3045 reflections measured on an automated diffractometer. The oxygen atoms at C(3) and C(17) at either ends link the molecules together in a head to tail fashion. The hydroxy groups of the solvent molecules also take part in linking the molecules sideways through the hydroxy groups.