Structural studies on bioactive compounds. 4. A structure-antitumor activity study on analogs of N-methylformamide

• Published in: Journal of medicinal chemistry 1986-06, Vol.29 (6), p.1046-1052
• Main Authors: Gate, E. Nicholas, Threadgill, Michael D, Stevens, Malcolm F. G, Chubb, David, Vickers, Lisa M, Langdon, Simon P, Hickman, John A, Gescher, Andreas
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Female; Formamides - metabolism; Formamides - pharmacology; Hydroxylation; Lymphoma - drug therapy; Magnetic Resonance Spectroscopy; Mice; Ovarian Neoplasms - drug therapy; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00156a024

A series of derivatives of N-methylformamide (NMF), an experimental antitumor agent, has been prepared, having the general formula R3C(X)NR1R2 where R1 = H, CH3, CD3, CH2CF3, CH2CH2Cl, cyclopropyl, C2H5, CH2OH, CH2OR, CH2N(CH3)2; R2 = H, CH3; R3 = H, CF3, CCl3, CH3, Ph, NHCH3, N(CH3)2; and X = O, S, NH. A further short series of "push-pull" olefins of the general formula R1R2C = CHNR3R4 has been synthesized where R1 = H, CH3 and R2 = H, NO2, CN, CHO, CH3 and R3 = H and R4 = H, CH3, morpholino. These compounds have been tested for activity against the M5076 ovarian sarcoma and the TLX5 lymphoma in mice. NMF was by far the most potent agent of both series with activity against both tumors. Some other compounds showed weak activity, but there is a rigorous structural requirement for activity and most analogues were inactive. Certain members of the series exist as equilibrium mixtures of rotamers about the amide or pro-amide bonds as shown by NMR.