Alummoottil V. Joshua

Molecular mechanism of binding of pyrrolo(1,4)benzodiazepine antitumour agents to deoxyribonucleic acid--anthramycin and tomaymycin.

Abstract The synthesis of 3,3-dimethyl-4-oxo-3,4-dihydroquinoline (16), 3,3-dimethyl-4-oxo-2-methoxy-1,2,3,4-tetrahydroquinoline (17). and of 1 1a-S-pyrrolo(1, 4)benzodiazepine (21) as models to study the mechanism of action of the pyrrolo(1, 4)benzodiazepine antitumour antibiotics is described. Both 16 and 21 readily add nucleophiles to the imine bond but only 21, like the parent antibiotics, readily produces covalent attachment to DNA. The extent of binding of the pyrrolo(1, 4)benzodiazepine antibiotics to DNA, measured by suppression of ethidium fluorescence, is proportional to the antibiotic concentration and is partly reversed by a heat-denaturation-renaturation cycle. The extent of binding of the pyrrolo(1, 4)benzodiazepines to DNA is also promoted by lower pH (range 4.7 to 9) and higher temperatures (range 0–51°), and the DNA-antibiotic complex is stable to dialysis. There is no evidence that these antibiotics intercalate into DNA, assayed by calf thymus topoisomerase, but they are more reactive toward relaxed PM2-DNA than to supercoiled DNA. Examination of DNA binding of the antitumour antibiotics and their analogues to DNAs of different base composition and separately in conjunction with sequence specific binding agents showed little base preference for the binding. Reaction of the pyrrolo(1, 4)benzodiazepines with DNA produces neither depurination, assayed with endonuclease VI, nor strand scission. A free or potential carbinolamine or imine function at the 10, 11 positions in a benzo(1, 4)diazepine nucleus is an absolute requirement for DNA binding or for reaction with nucleophiles. These results with the native antibiotics and their analogues, in particular the N-acetyl compound 7 favor a molecular mechanism of action by acid-promoted addition of biological nucleophiles to the 10, 11 conjugated imine closely analogous to that proposed for the antitumour agent maytansine.

Interactions of the glycopeptide antitumor antibiotics bleomycin and tallysomycin with deoxyribonucleic acid in vitro

Abstract Tallysomycin (TLM), an experimental glycopeptide antitumor antibiotic related to bleomycin (BLM), at a concentration of 4.8 × 10 −5 M sequesters Fe 2+ and nicks circular DNA to 75–80 per cent in 45 min. The DNA scission reaction which requires oxygen and is suppressed by other divalent ions and by EDTA is pH dependent and shows optima at 9.6 and 11.2. BLM under comparable conditions shows three pH optima at 9.3. 10.6 and 11.2. TLM binds to DNA more strongly than BLM. especially at pH 7.0 to 4.7. The three intermediates, O − 2 , H 2 O 2 and OH, are implicated in the DNA scission by tallysomycin as indicated by (1) inhibition by Superoxide dismutase, (2) inhibition by catalase. and (3) e.s.r. detection of the spin-trapped PBN · OH nitroxide radical, respectively. The A,T-specific DNA binding agents, netropsin and distamycin, enhance the TLM-induced cleavage by 7 per cent and 9.5 per cent, while G.C-specinc agents, olivomycin and chromomycin-A 3 , enhance the scission by 15 per cent and 16 per cent, respectively. TLM and BLM suppress the extent of psoralen-photo-induced DNA cross-linking by 24 per cent and 53 per cent, respectively. TLM with the spermidine moiety truncated by spermidine oxidase binds to DNA with less efficiency (5.5 per cent) than does the parent antibiotic (19 per cent). However, the modified TLM also sequesters Fe 2+ and nicks DNA with comparable efficiency to TLM under similar conditions. This suggests (1) that the spermidine moiety is not involved in binding Fe 2+ at the ‘active site’ of the antibiotic responsible for DNA cleavage, and (2) that in binding to DNA, at least of TLM Fe 2+ , intercalation by the bithiazole moiety is more significant than electrostatic attraction by the spermidine chain. The results are in accord with a mode of action in which TLM sequesters Fe 2+ . binds to DNA and produces OH radicals close to the duplex to cleave the latter. A chemical mechanism is suggested for this process.

Bleomycin models. Haemin–acridines which bind to DNA and cause oxygen-dependent scission

Haemin–acirdines intercalate into duplex DNA via the acridine moiety and, in the presence of reducing agents, cause oxygen dependent scission and show antileukemic properties analogous to the action of the glycopeptide antibiotic bleomycin.

Total synthesis of indole and dihydroindole alkaloids. XI.1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

A detailed study involving the Polonovski-type coupling of vindoline (2) with several novel catharanthine derivatives is described. Coupling of vindoline (2) with the N-oxide intermediate of 3β,4β-epoxydihydrocatharanthine (1) provides a laboratory synthesis of the bisindole alkaloid leurosine (3, R=CO2CH3) and an unambiguous proof of the stereochemistry of the epoxide function in that alkaloid. The coupling of 2 with the N-oxides of 3α,4α-epoxydihydrocatharanthine (4) and 4α-hydroxydihydrocatharanthinic acid lactone (6) provide the rearranged bisindole products 5, 7, and 8.

Radioiodinated N -[3-(4-morpholino)propyl]- N -methyl-2-hydroxy-5-iodo-3-methylbenzylamine (ERC9): a new potential melanoma imaging agent

Abstract. The role of nuclear medicine in the management of patients with malignant melanoma has expanded in recent years with the introduction of lymphoscintigraphy and sentinel lymph node biopsy, intense interest in positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxyglucose (18F-FDG) as a tracer, and encouraging reports of several new single-photon-emitting radiopharmaceuticals. While PET imaging with FDG exhibits a high sensitivity for imaging patients with melanoma, specificity may not be as high and access to the technology remains limited. Single-photon emission tomography (SPET) imaging remains standard technology for most nuclear medicine departments. We report a novel radiopharmaceutical – radioiodinated N-[3-(4-morpholino)propyl]-N-methyl-2-hydroxy-5-iodo-3-methylbenzylamine (ERC9) – which appears to show a sensitivity and specificity that are commensurate with expectations of a radiopharmaceutical for routine clinical imaging. In this phase II trial, 110 patients at risk for recurrence, with suspected recurrence or being restaged have been imaged with this novel tracer, demonstrating an overall sensitivity of 91% and specificity of 89%. The results of our study support a phase III trial to establish the clinical role of ERC9 in staging melanoma patients at presentation who are at high risk for metastasis, or restaging patients with known relapse to assess the extent of their disease, particularly if therapy or enrollment into a clinical trial is being considered.

Synthesis and evaluation of novel 4-amino-4,6-androstadiene-3,17-dione : An analog of formestane

Synthesis of 4-amino-4,6-androstadiene-3,17-dione 7, an analog of formestane used in breast cancer therapy as an aromatase inhibitor, from 4-acetoxy-4-androstene-3,17-dione 2 is described. This is the first report of a 4-amino diene (4,6) system in this series of molecules. The new (7) and reported molecules were screened by the National Cancer Institute (NCI, Bethesda, USA) for in vitro antitumor activity against 60 human cancer cell lines. Molecule 7 showed best activity against breast cancer cell line (MCF-7).

Total synthesis of indole and dihydroindole alkaloids. X.1,2 The preparation of novel oxygenated catharanthine derivatives

Detailed investigations involving the electrophilic attack of various reagents on the 3,4-double bond of catharanthine derivatives (e.g. 3, R = O) furnished a series of novel derivatives of potenti...

New Short Synthesis of (5)‐2,3‐Dimethoxy‐N‐[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐5‐iodobenzamide: Dopamine D2 Receptor

Abstract A new short and highly efficient synthesis of (5)‐2,3‐dimethoxy‐N[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐5‐iodobenzamide (epidepride, 1) from 3‐methoxy‐salicylaldehyde (o‐vanillin, 2) and 3‐methoxysalicyclic acid (6) was achieved by employing a new iodination method with iodine monochloride and iodine nitrate under basic conditions.Abstract A new short and highly efficient synthesis of (5)‐2,3‐dimethoxy‐N[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐5‐iodobenzamide (epidepride, 1) from 3‐methoxy‐salicylaldehyde (o‐vanillin, 2) and 3‐methoxysalicyclic acid (6) was achieved by employing a new iodination method with iodine monochloride and iodine nitrate under basic conditions.

Stereochemistry and regiochemistry of the addition of lodonium nitrate to alkenes

Iodonium nitrate in the presence of pyridine adds trans-stereospecifically and regiospecifically to a series ofZ–E pairs of alkenes to give iodoalkyl nitrate esters and iodoalkyl pyridinium nitrates. The stereochemistry of the products was confirmed by relating them chemically with known compounds. Addition to the less hindered (Z)-[β-2H]styrene is also stereospecific, eliminating the possibility of restricted rotation during addition. Ring closure by neighbouring sulphur in the addition of iodonium nitrate to 1-allyl-3,3-diethylthiourea affords a thiazole. The failure to obtain addition and phenyl migration in 3,3,3-triphenylpropene may be due to steric hindrance of the approach of the [IPy2]+ complex. The latter was isolated as its nitrate salt and was shown to undergo a stoicheiometric and stereospecific addition to (E)-4,4-dimethylpent-2-ene to give erythro-2-iodo-1,3,3-trimethylbutyl nitrate (IIIa).