Self-immolative nitrogen mustards prodrugs cleavable by carboxypeptidase G2 (CPG2) showing large cytotoxicity differentials in GDEPT.
Nineteen novel potential self-immolative prodrugs and their corresponding drugs have been synthesized for gene-directed enzyme prodrug therapy (GDEPT) with carboxypeptidase G2 (CPG2) as the activating enzyme. The compounds are derived from o- and p-amino and p-methylamino aniline nitrogen mustards. Their aqueous stability, kinetics of drug release by CPG2, and cytotoxicity in the colon carcinoma cell line WiDr, expressing either surface-tethered CPG2 (stCPG2(Q)3) or control beta-galactosidase, are assessed. The effect of various structural features on stability, kinetics of activation, and biological activity is discussed. The p-methylamino prodrugs are the most stable compounds from this series, with the largest cytotoxicity differentials between CPG2-expressing and nonexpressing cells. The most potent compounds in all series are prodrugs of bis-iodo nitrogen mustards. 4-[N-[4'-Bis(2' '-iodoethyl)aminophenyl]-N'-methylcarbamoyloxymethyl]phenylcarbamoyl-l-glutamic acid, compound 39b, is 124-fold more cytotoxic to WiDr cells expressing CPG2 than to cells expressing beta-galactosidase. An additional six compounds show better cytotoxicity differential than the published N-[4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl]-l-glutamic acid (CMDA) prodrug.
Niculescu-Duvaz
Dan
D
CR-UK Centre for Cancer Therapeutics at the Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK.
Niculescu-Duvaz
Ion
I
Friedlos
Frank
F
Martin
Jan
J
Lehouritis
Panos
P
Marais
Richard
R
Springer
Caroline J
CJ
D000816:Aniline Mustard / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D018014:Gene Transfer Techniques; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D021281:Quantitative Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics / Q000378:metabolism*
C474149:4-(N-(4'-bis(2''-iodoethyl)aminophenyl)-N-methylcarbamoyloxymethyl)phenylcarbamoylglutamic acid; D018906:Antineoplastic Agents, Alkylating; D002219:Carbamates; D011355:Prodrugs; D018698:Glutamic Acid; D000816:Aniline Mustard; D011623:gamma-Glutamyl Hydrolase