New pyrrolobenzodiazepine (PBD) dimers have been developed that are composed of two DC-81 subunits tethered to their C8 positions through piperazine moiety side-armed with alkaneoxy linkers (composed of 2–5 carbons). DNA thermal denaturation studies show that after 18 h of incubation with calf thymus DNA at a 1:5 ligand/DNA ratio, one of them, 6a, increases the ΔTm value by 24.0 °C. Thus, incorporation of a piperazine moiety instead of an inert alkanedioxy linker alone significantly enhances the DNA binding ability, and the analogous dimer 4 that lacks a piperazine moiety in the linker spacer elevates melting by only 15.1 °C under identical experimental conditions. This illustrates the effect of introducing a piperazine ring in the middle of such an alkanedioxy linker which produces several hydrophobic interactions and could also achieve a superior isohelical fit within the DNA minor groove. Interestingly, these dimers 6a–d are significantly more cytotoxic than 4 in a number of human cancer cell lines, in particular, compound 6c is highly potent for almost all the nine human cancer cell lines.

A series of C2-exo-fluorounsaturated pyrrolobenzodiazepines (PBDs) have been synthesized. These C2-exo-fluorounsaturated PBD dimers have exhibited remarkable DNA-binding affinity.

Two moieties of epipodophyllotoxin have been linked at C4-position to provide novel bisepipodophyllotoxin analogues. These have been evaluated for their anticancer potential and DNA-topoisomerase 11 poisoning activity. Most of these analogues have exhibited promising in vitro anticancer activity against different human tumour cell lines and interestingly 4'-O-methylated analogues have shown increased cytotoxic activity. Similarly, the DNA-topo 11 poisoning activity tested for these compounds has not only exhibited the DNA cleavage potential comparable to etoposide, but for some compounds this cleavage potential is superior to etoposide. Further, an interesting structure-activity relationship of these epipodophyllotoxin dimers have been generated on the basis of GI(50) values. The equations indicated that GI(50) activity is strongly dependent on structural and thermodynamic properties. These QSAR results are discussed in conjunction with conformational analysis from molecular modelling studies. QSAR models developed in these studies will be helpful in the future to design novel potent bispodophyllotoxin analogues by minor structural modifications. (C) 2004 Elsevier Ltd. All rights reserved.

A simple and efficient dethioacetalization has been carried out by employing FeCl3 . 6H(2)O under mild conditions. This method has been investigated for the synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine antitumour antibiotics via deprotective cyclization process.

Reaction of a variety of azido compounds with FeSO4·7H2O/NH3 results in quantitative yields of the corresponding amino compounds. This reductive methodology has been extended towards the synthesis of pyrrolo[2,1-c][1,4]benzodiazepine antibiotics.

ω-Azido carbonyl compounds on reaction with trimethylsilyl iodide (in situ prepared from TMSCl/NaI) led to the formation of diazepine imines in good yields under mild conditions. This methodology has been applied to the parent unsubstituted pyrrolobenzodiazepine, the natural product DC-81 and its dimers.

An efficient synthesis of pyrrolo[2,1-c][1,4]benzodiazepines via reductive cyclization of ω-azido/nitrocarbonyl compounds employing samarium iodide is described. This methodology has also been extended for the preparation of DNA-crosslinking DC-81 dimers.

A new extremely facile and efficient cleavage of allyl ethers is developed employing chlorotrimethylsilane/sodium iodide.

N-Substituted phthalimides and naphthalimides have been obtained in good to excellent yields, employing chlorotrimethylsilane and sodium iodide (in situ generation of iodotrimethylsilane) from corresponding azides and anhydrides under mild conditions.

Chlorotrimethylsilane — sodium iodide reagent (in situ generation of iodotrimethylsilane)in acetonitrile reduces alkyl and aryl/aroyl azides to the corresponding amines/amides in excellent yields under neutral and mild conditions.