S. A. Mizsak

The structure of CC-1065, a potent antitumor agent and its binding to DNA

The crystal and molecular structure of a potent antitumor agent, CC1065 (C37H33N708), has been determined, and circular dichroism studies have demonstrated a strong interaction between CC-1065 and DNA. The triclinic unit cell, space group P1, of dimensions a = 11.063 (3) A, b = 13.311 (2) A, c = 13.405 (2) A, a = 85.18 (1)O, @ = 99.52 (l), and y = 103.36 (2)O, contains two CC-1065 molecules and disordered solvent molecules (two methanols and three waters). Intensity data for 6284 reflections were collected at -155 (2) OC; the final R value was 0.08 for 241 1 significant high-angle reflections. NMR spectroscopy was very important in assigning kinds of atoms. The CC-1065 molecule consists of three substituted benzodipyrrole moieties linked by amide bonds. One terminal moiety has a cyclopropyl ring; the only asymmetric carbons in the molecule are at the cyclopropyl ring junctures. The two symmetry-independent molecules have the same configuration, but the absolute configuration is not known. The CC-1065 molecules are curved and somewhat twisted with the outer periphery hydrophilic and the inner surface lipophilic. The interaction between CC-1065 and a number of DNA polymers was studied by circular dichroism. The CD effect requires double-stranded DNA and is strongest with poly(dA-dT):poly(dA-dT). A number of antitumor agents a re known to bind to deoxyribonucleic acid by nonintercalative means.-s Netropsin is an oligopeptide that binds preferentially to poly(dA):poly(dT) and is thought to interact through hydrogen bonds in the minor groove of DNA.s2 Anthramycin is a pyrrolo[ 1,4] benzodiazepine that binds covalently to guanine in the minor g r o ~ v e . ~ , ~ Braithwaite and Baguley have investigated netropsin, distamycin, and several bisamidine and bisquaternary ammonium heterocyclic drugs by viscometric, spectrophotometric, and fluorometric methods, and propose that they all bind in the minor groove of the D N A double helix.5 A new antitumor agent, CC-1065, also binds to D N A without intercalation.6 CC-1065 is produced by a soil culture, streptomyces ~ e l e n s i s , ~ and was isolated in pure form8 and found to be significantly more cytotoxic in vitro than actinomycin, vinblastine, or maytansine? In vivo, CC-1065 is highly active against a variety of mouse tumors,* and, as a result, has been selected by the (1) (1) Berman, H. M.; Neidle, S.; Zimmer, C.; Thrum, H. Biochim. (2) Wartell, R. M.; Larson, J. E.; and Wells, R. D. J . Bio!. Chem. 1974, Biophys. Acta 1979, 561, 124-131.

Nodusmicin: The structure of a new antibiotic

Abstract The structure of nodusmicin 1, established by spectral, chemical and x-ray crystallographic techniques, contains a 10 membered lactone ring bonded to an oxygen-bridged octahydronaphthalene, a new antibiotic class.

The addition of amines to 3-bromochromone and 6-bromofurochromone. An unexpected ring contraction of the pyrone ring.

Abstract Addition of amines to 3-bromochromone and 6-bromofurochromone results in a novel ring contraction of the pyrone ring.

PALDIMYCINS A AND B AND ANTIBIOTICS 273a2α AND 273a2β

Paldimycin (antibiotic 273a1) and antibiotic 273a2 as well as their individual components, paldimycins A (273a1 alpha) and B (273a1 beta) and antibiotics 273a2 alpha and 273a2 beta were synthesized from paulomycin, paulomycin A and paulomycin B, respectively, by reacting with N-acetyl-L-cysteine. The semisynthetic antibiotics had chromatographic behavior (TLC, HPLC) and physical and chemical properties identical to the properties of the corresponding antibiotics produced by Streptomyces paulus.

The stereospecific synthesis of spectinomycin

Abstract The first synthesis of spectinomycin, a complex and sensitive antibiotic, is described. The synthesis, which requires only four steps from known materials, has flexibility for modifying either half of the molecule.

Mechanistic aspects of a novel, 1,2-3,4 reductive-fragmentation that establishes four stereocenters in a single step

Reduction of a β-furanyl unsaturated ketone with LiAlH4, LiAlD4 or sodium bis(methoxyethoxy)aluminum hydride (SMEAH) results in a novel reductive-fragmentation in which four elements of stereochemistry are established in a single step.

Mechanistic and stereochemical aspects of the 1,2–3,4 hydride reduction of enones

Abstract A unique mode of metal hydride reduction of unsaturated ketones is described which proceeds with a high degree of regio- and stereocontrol.