Maruta Boyd

Hypoxia-Activated Prodrugs: Substituent Effects on the Properties of Nitro seco-1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) Prodrugs of DNA Minor Groove Alkylating Agents

Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.

Synthesis, DNA interactions and biological activity of DNA minor groove targeted polybenzamide-linked nitrogen mustards

A series of polybenzamide DNA minor groove binding ligands bearing either one or two monofunctional mustards have been synthesised, and their cytotoxicities and interactions with DNA have been studied. Analogues with two alkylating functions (e.g. compounds 7 and 14) are the most cytotoxic, with 7 being 1000-fold more potent than the clinical mustard chlorambucil against P388 leukemia in culture, as well as being more potent in vivo. Monofunctional analogues were also significantly more cytotoxic than chlorambucil, despite bearing much less reactive mustard species. These results support the concept that targeting nitrogen mustard alkylating agents to DNA by attachment to DNA-affinic carriers can greatly enhance cytotoxicity due to alkylation, and that even for such DNA-targeted mustards, crosslinking is a more toxic event than monoalkylation. Close analogues of 7 differing only in their radius of curvature, appear to alkylate and crosslink DNA in similar fashion, yet have widely differing cytotoxicities. The most cytotoxic compound (7) possesses a geometry most complementary to that of duplex DNA, suggesting that the most toxic lesions are those which result in least DNA distortion, thus being less easily recognised by DNA repair systems.

Structure of 3-methoxycarbonyl-1-methyl-4-nitropyrazole-5-carboxylic acid monohydrate

C 7 H 7 N 3 O 6 .H 2 O, M r =247.16, orthorhombic, Fdd2, a=31.535 (8), b=14.313 (5), c=9.446 (3) A, Z=16, V=4263.6 A 3 , D x =1.54 g cm -3 , λ(Mo Kα)=0.71069 A, μ=1.31 cm -1 , F(000)=2048, room temperature, final R=0.0368 for 1223 observed reflections. The pyrazole ring is planar. The methoxycarbonyl, nitro and acid groups make angles of 8.1, 74.5 and 16.7 o , respectively, with the pyrazole ring. The water of crystallization forms strong hydrogen bonds with the acid proton of one molecule and the unsubstituted pyrazole N atom of a symmetry-related molecule

Crystallographic and oxygen-17 NMR studies of nitro group torsion angles in a series of 4-alkylaminonitroquinolines designed as hypoxia-selective cytotoxins

Nitro group torsion angles have been determined by 17O NMR spectroscopy for a series of 4-(alkyl-amino)nitroquinolines and their ortho-methyl-substituted analogues. Crystal structures were determined for two pairs of compounds, to further evaluate the validity of Boykins equation. The crystallographic torsion angles were used to calculate a modified version of the equation, relating 17O chemical shift values (δ) and nitro group torsion angles (θ), applicable to N-heterocyclic systems, as follows: θ= 1.18(±0.13)δ– 661. This equation was then used to compute nitro group torsion angles for the nitroquinolines. Unhindered nitro groups were close to coplanar with the aromatic ring as expected, while addition of one ortho methyl group increased the torsion angle to ca. 30°. The 5-nitro derivative had a nitro group torsion angle of ca. 80°, due to peri interactions with the 4-aminoalkyl sidechain. The 8-nitroquinoline derivative is the first example of a nitroaromatic with a peri aromatic nitrogen substituent, and the torsion angle of 70–78°(measured by both NMR spectroscopy and X-ray crystallography) indicates the substantial steric effect of the nitrogen lone pair. Addition of a 7-methyl group in the other nitro ortho position of this compound results in the nitro group being virtually at right angles to the ring (torsion angle 86°). A comparison was made between the measured torsion angles and those calculated using the AM1 and PM3 methods. The former underestimates the nitro torsion angles in these systems, while the PM3 method significantly overestimates them. Overall, no simple relationship exists in the nitroquinolines between nitro group torsion angles and the reduction potentials of the compounds.