title: Synthesis and antitumor activity of 4-aminomethylthioxanthenone and 5-aminomethylbenzothiopyranoindazole derivatives.
abstract: Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.
authors.affiliation: Departments of Medicinal Chemistry and Oncopharmacology, Sanofi Winthrop Inc., 9 Great Valley Parkway, Malvern, Pennsylvania 19355, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Perni
authors.forename: M P
authors.initials: MP
authors.lastname: Wentland
authors.forename: J I
authors.initials: JI
authors.lastname: Huang
authors.forename: R G
authors.initials: RG
authors.lastname: Powles
authors.forename: S
authors.initials: S
authors.lastname: Aldous
authors.forename: K M
authors.initials: KM
authors.lastname: Klingbeil
authors.forename: A D
authors.initials: AD
authors.lastname: Peverly
authors.forename: R G
authors.initials: RG
authors.lastname: Robinson
authors.forename: T H
authors.initials: TH
authors.lastname: Corbett
authors.forename: J L
authors.initials: JL
authors.lastname: Jones
authors.forename: K C
authors.initials: KC
authors.lastname: Mattes
authors.forename: J B
authors.initials: JB
authors.lastname: Rake
authors.forename: S A
authors.initials: SA
authors.lastname: Coughlin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013892:Thioxanthenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D007191:Indazoles; D007364:Intercalating Agents; D011714:Pyrans; D013892:Thioxanthenes; D059005:Topoisomerase II Inhibitors