title: Benzoyl and cinnamoyl nitrogen mustard derivatives of benzoheterocyclic analogues of the tallimustine: synthesis and antitumour activity.
abstract: A series of benzoyl and cinnamoyl nitrogen mustards tethered to different benzoheterocycles and to oligopyrroles structurally related to netropsin consisting of two pyrrole-amide units and terminating with an amidine moiety have been synthesised and a structure--activity relationship determined. Derivatives 3--10 have been evaluated for their sequence selective alkylating properties and cytotoxicity against human K562 leukaemia cells. They are 2- to 50-fold less cytotoxic than tallimustine, with compound 8 being the most potent member of this series. Among tallimustine isosters, the compounds with an indole 3 or benzothiophene 6 are 4-fold less cytotoxic than tallimustine, while the compounds with an N-methyl indole or benzofuran showed a 7- and 14-fold reduced cytotoxic potency, respectively. Our preliminary results indicate that these derivatives preferentially bind to AT-rich sequence with a sequence selectivity similar to tallimustine.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy. pgb@dns.unife.it
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Maria
authors.initials: M
authors.lastname: Giovanna Pavani
authors.forename: Maria
authors.initials: M
authors.lastname: del Carmen Nunez
authors.forename: John P
authors.initials: JP
authors.lastname: Bingham
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry; D001665:Binding Sites; D002934:Cinnamates / Q000737:chemistry; D004247:DNA / Q000378:metabolism; D004214:Distamycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D020014:K562 Cells / Q000187:drug effects; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018906:Antineoplastic Agents, Alkylating; D001565:Benzoates; D002934:Cinnamates; D004214:Distamycins; D006571:Heterocyclic Compounds; D009588:Nitrogen Mustard Compounds; C066900:tallimustine; D004247:DNA