Design, synthesis, and evaluation of new cyclophosphamide-based anticancer prodrugs

Miscellaneous · Fri Jan 01 00:00:00 EST 1993

OSTI ID:7009312

Moon, Ki-Young

Cyclophosphamide (CP,1) is a prodrug that is activated by hepatic microsomal mixed-function oxidase (MFO) catalyzed C[sub 4]-hydroxylation. The resulting 4-hydroxycyclophosphamide (4-OH-CP) undergoes ring opening to aldophosphamide (Aldo), followed by generation of cytotoxic phosphoramide mustard (PDA,2) and acrolein by [beta]-elimination. The cytotoxic activity of CP is attributed to the aziridinium ion species derived from PDA that cross-links interstrand DNA. The aim of this research is to design, synthesize, and evaluate new cyclophosphamide-based alkylating agents to achieve improved therapeutic efficacy against neoplastic cells. Benzyl phosphoramide mustard (Benzyl PDA,4), 2.4-difluorobenzyl phosphoramide mustard (2,4-Difluorobenzyl PDA,5) and methyl phosphoramide mustard (Methyl PDA,6) were examined as lipophilic, chemically stable prodrugs of PDA (2). These phosphorodiamidic esters were designed to undergo biotransformation by hepatic microsomal enzymes to produce 2 without generation of acrolein and to be active against CP-resistant tumor cells. Several N-methyl-4-(alkylthio)cyclophosphamide derivatives were synthesized and examined as chemically stable, biooxidative prodrugs of 4-OH-CP, the activated species of CP. All of the prodrugs underwent N-demethylation in a time-dependent manner when incubated with rat hepatic microsomes, which resulted in formation of formaldehyde as well as alkylating species. Among the prodrugs, N-methyl-4-(diethyldithiocarbamoyl)cyclophosphamide (N-CH[sub 3]-4-DDTC-CP,15) showed exceptional in vitro cytotoxicity against 3T3 cells as well as against a panel of human tumor cell lines, with a particular sensitivity to leukemia and small cell lung cancer cell lines. Preliminary in vivo antitumor evaluation against L1210 leukemia in mice showed that all of the prodrugs were active.

• Research Organization: Saint John's Univ., Jamaica, NY (United States)
• OSTI ID: 7009312
• Resource Relation: Other Information: Thesis (Ph.D.)
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
37 INORGANIC
ORGANIC
PHYSICAL AND ANALYTICAL CHEMISTRY
ANTINEOPLASTIC DRUGS
CHEMICAL PREPARATION
DESIGN
PHARMACOLOGY
ENDOXAN
ANIMAL CELLS
MICE
ALKYLATING AGENTS
ANIMALS
DRUGS
IMMUNOSUPPRESSIVE DRUGS
MAMMALS
RODENTS
SYNTHESIS
VERTEBRATES
550600* - Medicine
400201 - Chemical & Physicochemical Properties