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.
Angelino
N J
NJ
Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Bernacki
R J
RJ
Sharma
M
M
Dodson-Simmons
O
O
Korytnyk
W
W
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D002236:Carbohydrate Conformation; D002462:Cell Membrane / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D006595:Hexosamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D007939:Leukemia L1210 / Q000188:drug therapy*; D008358:Mannose / Q000031:analogs & derivatives* / Q000737:chemistry*; D051379:Mice; D008811:Mice, Inbred DBA; D012794:Sialic Acids / Q000737:chemistry
D000970:Antineoplastic Agents; D006595:Hexosamines; D012794:Sialic Acids; C008322:mannosamine; D008358:Mannose; C002022:N-acetylmannosamine