Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy

• Published in: Journal of medicinal chemistry Vol. 60; no. 13; pp. 5834 - 5856
• Main Authors: Tercel, Moana, Lee, Ho H, Mehta, Sunali Y, Youte Tendoung, Jean-Jacques, Bai, Sally Y, Liyanage, H. D. Sarath, Pruijn, Frederik B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.07.2017; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Hypoxia - drug effects; Cell Line, Tumor; Chemistry, Medicinal; Combined Modality Therapy; Drug Screening Assays, Antitumor; Female; Humans; Indoles - chemistry; Indoles - pharmacology; Indoles - therapeutic use; Life Sciences & Biomedicine; Mice; Mice, Nude; Nitro Compounds - chemistry; Nitro Compounds - pharmacology; Nitro Compounds - therapeutic use; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Ovarian Neoplasms - radiotherapy; Ovary - drug effects; Ovary - pathology; Ovary - radiation effects; Pharmacology & Pharmacy; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Pyrrolidinones - therapeutic use; Science & Technology; PHASE-II TRIAL; DRUG CONJUGATE; ACTIVATED PRODRUG; SULFONATE LEAVING GROUPS; TISSUE PENETRATION; SECO-CBI-TMI; MALIGNANT-MELANOMA; ANTITUMOR-ACTIVITY; CANCER-THERAPY; BINDING SUBUNITS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b00563

A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pK a 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of γ irradiation 50 at 42 μmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment were completely tumor free at day 100.