The non-covalent interaction of pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones with DNA.
A series of 15 pyrrolo[2, 1-c] [1, 4]benzodiazepine-5, 11-diones has been synthesized and evaluated for in vitro DNA binding by thermal denaturation and fluorescence quenching studies with calf thymus (CT) DNA. The results indicate that two compounds of the series, 7 and 8, elevate the melting point of DNA by 2.9 +/- 0.6 and 3.3 +/- 0.8 K, respectively. Similarly, a significant quenching of the fluorescence of the dihydroxy analogue 8 was observed upon interaction with CT-DNA. As controls, the dihydroxy isomer 9 with the reverse stereochemistry at C2 and the non-substituted parent dilactam 12, failed to increase the DNA melting point or exhibit significant quenching upon interaction with DNA. In addition, preliminary experiments with GC- and AT-rich polymers suggest some sequence-dependent properties for dilactams 7 and 8. Overall, these results indicate a highly specific structural requirement for DNA binding. Molecular modelling with d(GTAGATC), d(GCAGATC) and d(GCGTAGC) duplex sequences has provided a model based on hydrogen bonding between the dihydroxy dilactam 8 and DNA, that rationalizes some of the results obtained. It is possible that the observed interactions represent the non-covalent (binding) component of the interaction of covalently-bonding anthramycin-type anti-tumour antibiotics with DNA.
Division of Medicinal Chemistry, School of Pharmacy and Biomedical Sciences, Portsmouth Polytechnic, UK.
G B
GB
Jones
C L
CL
Davey
T C
TC
Jenkins
A
A
Kamal
G G
GG
Kneale
S
S
Neidle
G D
GD
Webster
D E
DE
Thurston
D000876:Anthramycin / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000378:metabolism*; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D004347:Drug Interactions; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones; D011758:Pyrroles; D000876:Anthramycin; C003619:tomaymycin; D004247:DNA