Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer.

We report the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 16 synthesised through a new and efficient route, thus establishing that C2-C3-endo unsaturation enhances both cytotoxicity and DNA-binding affinity in A-Ring-linked PBD dimers but to a lesser extent than C2/C2'-exo-unsaturation. This new route has allowed the preparation of multi-gram quantities of the related clinical candidate 1 and should lead to more structurally diverse PBD dimer analogues.

CT colonography without cathartic preparation: feasibility study.

PURPOSE: To evaluate methods for contrast material labeling of stool in the unprepared colon for computed tomographic (CT) colonography and to determine their sensitivity for polyp detection. MATERIALS AND METHODS: Fifty-six patients with suspected or known polyps were assigned to five groups. Two to seven doses of 225 mL of dilute contrast material were orally administered during 24 or 48 hours. Transverse CT images were assessed for effectiveness of stool labeling. Colonoscopy was performed in all patients and was the standard. Two radiologists blinded to prior imaging and colonoscopic results assessed polyp detection. RESULTS: For each group, average stool labeling scores and ranges were as follows: 24 hour two dose, 16% and 8%-21%; 24 hour five dose, 53% and 27%-66%; 48 hour four dose, 38% and 22%-48%; 48 hour six dose, 68% and 54%-77%; and 48 hour seven dose, 88% and 75%-98%. Sensitivity for the two radiologists for the identification of patients with polyps 1 cm or larger for each group was as follows: 24 hour two dose, 50% and 67%; 24 hour five dose, 100% and 100%; 48 hour four dose, 58% and 75%; 48 hour six dose, 56% and 67%; and 48 hour seven dose, 100% and 80%. CONCLUSION: Ingestion of contrast material adequately labels stool for lesion identification; a 48-hour lead time and multiple doses of contrast material are required. Sensitivity for polyp detection in patients with adequate stool labeling approaches the sensitivity for polyp detection in prepared colons.

Effect of C2-exo unsaturation on the cytotoxicity and DNA-binding reactivity of pyrrolo[2,1-c][1,4]benzodiazepines.

A series of novel C2-exo unsaturated pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) has been synthesised via a versatile pro-C2 ketone precursor. C2-exo-unsaturation enhances both DNA-binding reactivity and in vitro cytotoxic potency.