- BENZODIAZEPINE DERIVATIVES
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The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formulae (I), (II) and (III). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.
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Page/Page column 138; 169; 170
(2019/07/17)
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- ALKYL 4- [4- (5-OXO-2, 3, 5, 11A-TETRAHYD0-5H-PYRR0L0 [2, 1-C] [1, 4] BENZODIAZEPINE-8-YLOXY) -BUTYRYLAMINO]-1H-PYRROLE-2-CARBOXYLATE DERIVATIVES AND RELATED COMPOUNDS FOR THE TREATMENT OF A PROLIFERATIVE DISEASE
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A compound of formula (I); or a salt or solvate thereof, wherein: the dotted line indicates the optional presence of a double bond between C2 and C3; R2 is selected from -H, -OH, =0, =CH2, -CN, -R, OR, halo, =CH-R, O-SO2-R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo, where R and R' are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and YRY, where Y is selected from O, S and NH and RY is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; each X is independently a heteroarylene group; n is from 1 to 6; and RE is C1-4 alkyl. The compound is useful for the treatment of proliferative diseases.
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Page/Page column 32-33
(2008/06/13)
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- Synthesis of DNA-sequence-selective hairpin polyamide platinum complexes
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Two DNA-sequence-selective hairpin polyamide platinum(II) complexes, containing pyrrole and imidazole heterocyclic rings, have been synthesised by different methods. A six-ring complex, selective for (A/T)GGG-(A/T) DNA sequences, was made by using solid-phase synthesis, whilst an eight-ring complex, selective for (A/ T)CCTG(A/T) DNA sequences, was made by utilising standard wet chemistry. Solid-phase synthesis resulted in a significantly higher yield, required less purification and is more efficient than the wet synthesis; as such, it is the preferred method for further work. The metal complexes were characterised by 1H and 195Pt NMR spectroscopy and ESI mass spectrometry. The two compounds provide a foundation for the synthesis of more complex molecules containing multiple hairpins and/or platinum groups.
- Taleb, Robin I.,Jaramillo, David,Wheate, Niai J.,Aldrich-Wright, Janice R.
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p. 3177 - 3186
(2008/02/05)
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- Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates
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A novel series of methyl ester-terminated CS-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5′-XGXWz (z = 3 ± 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.
- Wells, Geoff,Martin, Christopher R. H.,Howard, Philip W.,Sands, Zara A.,Laughton, Charles A.,Tiberghien, Arnaud,Woo, Chi Kit,Masterson, Luke A.,Stephenson, Marissa J.,Hartley, John A.,Jenkins, Terence C.,Shnyder, Steven D.,Loadman, Paul M.,Waring, Michael J.,Thurston, David E.
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p. 5442 - 5461
(2007/10/03)
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- DNA-TARGETED BENZOTRIAZINE 1,4-DIOXIDES AND THEIR USE IN CANCER THERAPY
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The present invention relates to DNA-targeted 1,2,4-benzotriazine- 1,4-dioxides and related analogues, to their preparation, and to their use as hypoxia-selective drugs and radiosensitizers for cancer therapy, both alone or in combination with radiation and/or other anticancer drugs.
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Page 108; 109
(2010/02/06)
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- Parallel synthesis and evaluation of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins defining the contribution of the DNA-binding domain
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The solution-phase, parallel synthesis and evaluation of a library of 132 (+)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of CC-1065 and the duocarmycins containing dimeric monocyclic, bicyclic, and tricyclic heteroaromatic replacements for the DNA-binding domain are described. This systematic study revealed clear trends in the structural requirements for observation of potent cytotoxic activity and DNA alkylation efficiency, the range of which spans a magnitude of ≥10 000-fold. Combined with related studies, these results highlight that the role of the DNA-binding domain goes beyond simply providing DNA-binding selectivity and affinity (10-100-fold enhancement in properties), consistent with the proposal that it contributes significantly to catalysis of the DNA alkylation reaction accounting for as much as an additional 1000-fold enhancement in properties.
- Boger,Schmitt,Fink,Hedrick
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p. 6654 - 6661
(2007/10/03)
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- Design, synthesis, DNA binding, and biological activity of a series of DNA minor-groove-binding intercalating drugs
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A group of pseudopeptides, molecular combination of the natural antitumor agents distamycin or netropsin and the anilinoacridine chromophore (which is related to the synthetic antileukemic drug amsacrine) has been synthesized. Their DNA binding properties were determined and discussed in terms of their structural differences and in relation to their observed base-dependent binding. Binding data are consistent with a model in which the acridine nucleus occupies an intercalation site and the netropsin or distamycin residue resides in the DNA minor groove. Cytostatic and cytotoxic activities against a murine cell line are reported, as well as significant differences in the inhibition of DNA synthesis.
- Bailly,Pommery,Houssin,Henichart
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p. 910 - 917
(2007/10/02)
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