Phosphonate-linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis, DNA-binding affinity and cytotoxicity.

Pyrrolobenzodiazepine-diethylphosphonate conjugates have been designed and synthesized that link through two different types of spacers that are simple alkane chain and also a piperazine moiety side-armed with the alkane chains. These pyrrolobenzodiazepine conjugates have exhibited remarkable DNA-binding affinity and improved solubility in water, a representative compound 7d showing promising in vitro cytotoxicity.

Structural studies on peanut lectin complexed with disaccharides involving different linkages: further insights into the structure and interactions of the lectin.

Crystal structures of peanut lectin complexed with Galbeta1-3Gal, methyl-T-antigen, Galbeta1-6GalNAc, Galalpha1-3Gal and Galalpha1-6Glc and that of a crystal grown in the presence of Galalpha1-3Galbeta1-4Gal have been determined using data collected at 100 K. The use of water bridges as a strategy for generating carbohydrate specificity was previously deduced from the complexes of the lectin with lactose (Galbeta1-4Glc) and T-antigen (Galbeta1-3GalNAc). This has been confirmed by the analysis of the complexes with Galbeta1-3Gal and methyl-T-antigen (Galbeta1-3GalNAc-alpha-OMe). A detailed analysis of lectin-sugar interactions in the complexes shows that they are more extensive when the beta-anomer is involved in the linkage. As expected, the second sugar residue is ill-defined when the linkage is 1-->6. There are more than two dozen water molecules which occur in the hydration shells of all structures determined at resolutions better than 2.5 A. Most of them are involved in stabilizing the structure, particularly loops. Water molecules involved in lectin-sugar interactions are also substantially conserved. The lectin molecule is fairly rigid and does not appear to be affected by changes in temperature.

Design, synthesis, and evaluation of mixed imine-amine pyrrolobenzodiazepine dimers with efficient DNA binding affinity and potent cytotoxicity.

Synthesis of mixed imine-amine pyrrolobenzodiazepine (PBD) dimers that are comprised of DC-81 and secondary amine (N10) of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three and five carbons) is described. These noncross-linking unsymmetrical molecules exhibit significant DNA minor groove binding ability and one of them 5b linked through the pentanedioxy chain exhibits efficient DNA binding ability (DeltaTm=11.0 degrees C) when compared to naturally occurring DC-81, 1 (DeltaTm=0.7 degrees C). The imine-amine PBD dimers exhibit promising in vitro antitumor activity in a number of human cancer cell lines.

Synthesis of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine-benzimidazole conjugates with remarkable DNA-binding affinity.

Two types of benzimidazoles have been synthesized and linked to DC-81 at C8-position through different alkyl chain spacers. These PBD conjugates have exhibited remarkable DNA-binding affinity, and a representative compound shows promising in vitro anticancer activity.

Synthesis and DNA binding affinity of novel A-C8/C-C2-exo unsaturated alkoxyamido-linked pyrrolo[2,1-c][1,4]benzodiazepine dimers.

The synthesis of novel A-C8/C-C2-exo unsaturated alkoxyamido-linked pyrrolo[2,1-c][1,4]benzodiazepine dimers is reported and these dimers show significant DNA binding affinity and they also exhibit moderate anticancer activity.

Synthesis of C8-linked pyrrolo[2,1-c][1,4]benzodiazepine-acridone/acridine hybrids as potential DNA-binding agents.

Pyrrolobenzodiazepine hybrids linked to acridone/acridine ring systems at C8-position have been designed and prepared that exhibit significant DNA-binding affinity, and a representative compound shows promising in vitro anticancer activity.

Solution and solid-state structure of N-acetamido-3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranosylamine.

High resolution 1H NMR and 13C NMR spectroscopic and single crystal X-ray structural analyses of N-acetamido-3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-galactopyranosylamine (1), a minor product of azidonitration reaction of 3,4,6-tri-O-acetyl galactal, are reported. The solution phase studies of 1 reflect that the compound exists in 4C1 conformation with cis-orientation of the substituents at C-1 and C-2. The solid-state structure of 1 reveals that a molecule of water is entrapped in the solid state of 1 and this water molecule serves to mediate N-H...O and C-H...O interactions.

Crystal structure of N-(benzyloxycarbonyl)aminoethyl-2,3,4,6-tetra-O-benzoyl-alpha-D-mannopyranoside: stabilization of the crystal lattice by a tandem network of N-H. . .O, C-H. . .O, and C-H. . .pi interactions.

Single crystal X-ray analysis of an aminoethyl mannopyranoside, namely, N-(benzyloxycarbonyl)aminoethyl-2,3,4,6-tetra-O-benzoyl-alpha-D-mannopyranoside (1), shows that the compound crystallizes in the monoclinic space group P2(1), with two molecules in the unit cell. The mannopyranoside unit adopts a distorted 4C(1) conformation. An analysis of the intermolecular interactions reveals a tandem network of N-H. . .O, C-H. . .O, and C-H. . .pi interactions responsible for stabilizing the crystal lattice.

Synthesis and antitumour activity of pyrene-linked pyrrolo [2,1-c]benzodiazepine hybrids.

Pyrene-linked pyrrolobenzodiazepine hybrids have been synthesized that exhibit potential anticancer activity in a number of human tumour cell lines. These hybrids also exhibit much enhanced DNA-binding ability in comparison to the parent pyrrolobenzodiazepine ring system (DC-81).

Synthesis and DNA-binding affinity of A-C8/C-C2 alkoxyamido-linked pyrrolo[2,1-c][1,4]benzodiazepine dimers.

The synthesis of new A-C8/C-C2 alkoxyamido-linked pyrrolo[2,1-c][1,4]-benzodiazepine dimers have been described in this report. These dimers exhibit significant DNA-binding ability with moderate anticancer activity.

The crystal structure of 1,2,3,4,6-penta-O-benzoyl-alpha-D-mannopyranose: observation of C-H...pi interaction as a surrogate to O-H...O interaction of a free sugar.

The crystal structure of the title compound was determined by X-ray crystallography. The compound crystallized in the orthorhombic space group P2(1)2(1)2(1) with four molecules in the unit cell with a=9.170(2), b=9.873 (2), c=38.831(8) A. The structure was refined to a R index of 0.041 for 7907 independent reflections. The mannopyranose unit adopts a distorted 4C1 conformation. The structure depicts unique network of C-H...pi interactions, very closely resembling the pattern of O-H...O interactions in free sugars. This intriguing and rare observation points to a notion that the supramolecular organization pertaining to a sugar is in-built in the pyranose ring itself.

Design and synthesis of novel chrysene-linked pyrrolo[2,1-c][1,4]-benzodiazepine hybrids as potential DNA-binding agents.

Chrysene-linked pyrrolobenzodiazepine hybrids have been prepared that possess cytotoxicity in some cancer cell lines. They also exhibit promising DNA-binding affinity and this is supported by molecular modeling studies.

Synthesis of C-8 methanesulphonate substituted pyrrolobenzodiazepines as potential antitumour agents.

The facile synthesis of C-8 methanesulphonate substituted pyrrolobenzodiazepines is described. These have been prepared by linking the methanesulphonate at C-8 position with alkanol spacer and their in vitro cytotoxicity have been described.

Synthesis of novel C2 and C2-C8 linked pyrrolo[2,1-c][1,4]benzodiazepine-naphthalimide hybrids as DNA-binding agents.

Synthesis of C2 and C2-C8 linked pyrrolobenzodiazepine-naphthalimide hybrids have been prepared that exhibit significant DNA-binding affinity and cytotoxicity.

Design, synthesis, and evaluation of new noncross-linking pyrrolobenzodiazepine dimers with efficient DNA binding ability and potent antitumor activity.

New sequence selective mixed imine-amide pyrrolobenzodiazepine (PBD) dimers have been developed that are comprised of DC-81 and dilactam of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three to five and eight carbons). Thermal denaturation studies show that after 18 h of incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, one of them (5c) increases the DeltaT(m) value by 17.0 degrees C. Therefore, these unsymmetrical molecules exhibit significant DNA minor groove binding affinity and 5c linked through the pentanedioxy chain exhibits efficient DNA binding ability that compares with the cross-linking DSB-120 PBD dimer (DeltaT(m) = 15.4 degrees C). Interestingly, this imine-amide PBD dimer has been linked with a five carbon chain linker unlike DSB-120, which has two DC-81 subunits with a three carbon chain linker, illustrating the effect of the noncross-linking aspect by introducing the noncovalent subunit. The binding affinity of the compounds has been measured by restriction endonuclease digestion assay based on inhibition of the restriction endonuclease BamHI. This study reveals the significance of noncovalent interactions in combination with covalent bonding aspects when two moieties of structural similarities are joined together. This allows the mixed imine-amide PBD dimer with a five carbon chain linker to achieve an isohelical fit within the DNA minor groove taking in to account both the covalent bonding and the noncovalent binding components. This has been supported by molecular modeling studies, which indicate that the PBD dimer with a five carbon chain linker gives rise to maximum stabilization of the complex with DNA at the minor groove as compared to the other PBD dimers with three, four, and eight carbon chain linkers. The energy of interaction in all of the complexes studied is correlated to the DeltaT(m) values. Furthermore, this dimer 5c has significant cytotoxicity in a number of human cancer cell lines.

Synthesis of C-8 alkylamino substituted pyrrolo[2,1-c][1,4]benzodiazepines as potential anti-cancer agents.

The design and facile synthesis of C-8 alkylamino substituted pyrrolo[2,1-c][1,4]benzodiazepines is described. These have been prepared by linking the amines at C-8 position with propane spacer to improve solubility in water, and their in vitro cytotoxicity studies have been carried out.