Synthesis of nitrosourea derivatives of sucrose as central nervous system anticancer agents

Abstract

Nitrosourea derivatives of sucrose have been synthesized for the purpose of obtaining anticancer agents with activity against brain cancer. Two such compounds, 6,6'-dideoxy-6,6'-di(3-methyl-3-nitrosoureido) sucrose (13) and 1', 6,6'-trideoxy-1',6,6-tri(3-methyl-3-nitrosoureido) sucrose (14), and their respective acetylated derivatives 15 and 16 have been prepared from sucrose. Compounds 13 and 14 have demonstrated antitumor activity against both L1210 leukemia and ependymoblastoma brain tumor in mice.

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…Sucrose analogs 544 and 545 of SZT were synthesized and tested in vivo against the L1210 leukemia (Table ). The rationale for the synthesis of these compounds was that sucrose penetrates cell membranes of brain tumors but not those of normal brain tissue .…”

“…Sucrose appears to be a selective agent for absorption by the brain tumor cells, because it is too polar to pass through cell membranes by passive diffusion . The large molecular radius of 4−5 Å of sucrose prevents its passage through cell pores, and it is not actively transported into cells .…”

“…Reduction of the azido functions yielded the corresponding amines which were converted to their N -methylureas with methyl isocyanate. Nitrosation with dinitrogen trioxide produced the desired bis- and tris- N -methyl- N -nitrosourea analogs 544 and 545 …”

“…Nitrosation with dinitrogen trioxide produced the desired bis- and tris- N -methyl- N -nitrosourea analogs 544 and 545 56

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31 Anticancer Activity of Disaccharide N -Nitrosourea Analogs against Ip-Implanted Murine L1210 Lymphoid Leukemia compound no.R 1 dose a mg/kgILS max , f,g %survivors, h %ther ratio i,g ref(s)R = −CO−N(NO)−CH 3 544 OH 200 b 37 436 545 NHR 200 b 37 R = −CO−N(NO)−CH 2 CH 2 Cl 546 100 c 650 100 440 547 100 c 650 70 440 548 20 d 403 66 443 549 10 d 384 66 443 550 8 d 483 60 443 551 40 d 226 20 445 552 32 d 467 60 445 553 CH 3 100 e 711 11 446 554 (CH 3 ) 2 CH 100 e 700 18 555 (CH 3 ) 2 CHCH 2 100 e 733 83 556 CH 3 CH 2 CH(CH 3 ...…”

Sucrochemistry. Part 33. The selective pivaloylation of sucrose

“…Fraction 0 was the major component and was obtained as a syrup (5 g, 42%) by elution with chloroform-methanol (15 : 1 ; 1 1) and was shown to be the 1,6-di-O-pivaloylp-D-fiucto furanosy~6-O-pivaloy~-a-~-gfucopyranoside (22), [a],, +57" (Found: c , 54.6; H, 8.1. C27H46014 requires C, 54.6; H, 7.7%); m/z (pentakistrimethylsilyl ether) 475 (3979, 463 (l), 373 (9), 361 (7), 283 (12), 271 (49, 211 (5), 109 (28), 85 (31), and 57 (100).…”