naphthyridinomycin and cyanonaphthyridinomycin

In this tutorial review, which should be of general interest to synthetic organic chemists at large, recent progress in the total synthesis of the tetrahydroisoquinoline antitumor antibiotics cyanocycline A, naphthyridinomycin, bioxalomycin alpha2, and lemonomycin is highlighted in detail and some biological background information is given as well. Preparations of truncated derivatives and uncompleted synthetic approaches are also described. The literature coverage includes the newest research results through the year 2008.

Topics: Anti-Infective Agents; Antineoplastic Agents; Cell Line, Tumor; Humans; Hydroquinones; Molecular Structure; Naphthyridines; Oxazoles; Tetrahydroisoquinolines

A full account of our [C + NC + CC] coupling approach to the naphthyridinomycin family of natural products is presented, culminating in formal total syntheses of cyanocycline A and bioxalomycin β2. The key complexity-building reaction in the synthesis involves the Ag(I)-catalyzed endo-selective [C + NC + CC] coupling of aldehyde 7, (S)-glycyl sultam 8, and methyl acrylate (9) to provide the highly functionalized pyrrolidine 6, which was carried forward to an advanced intermediate (compound 33) in Fukuyama's synthesis of cyanocycline A. Since cyanocycline A has been converted to bioxalomycin β2, this constitutes a formal synthesis of the latter natural product as well. The multicomponent reaction-based strategy reduces the number of steps previously needed to assemble these complex molecular targets by one-third. This work highlights the utility of the asymmetric [C + NC + CC] coupling reaction in the context of a complex pyrrolidine-containing target and provides an illustrative guide for its application to other synthesis problems. The synthesis also fueled collaborative biological and biochemical research that identified a unique small molecule inhibitor of cell migration (compound 30).

Topics: Biological Factors; Molecular Conformation; Naphthyridines; Oxazoles; Stereoisomerism

Cyanocycline A was found to have a pKa of 6.6. Protonation of N14 was established by 1H NMR spectroscopy. In strongly acidic solution the oxazolidine ring opened irreversibly. A model was derived for the binding of naphthyridinomycin and cyanocycline A to the hexanucleotide duplex d(ATGCAT)2, by using the molecular mechanics and dynamics modules of AMBER 3.0. It involved protonation on the oxazolidine-ring nitrogen, reduction of the quinone ring to a hydroquinone, formation of an iminium ion with loss of the C7 substituent, noncovalent binding in the minor groove with the hydroquinone ring in the 3'-direction from guanine, and covalent binding to the 2-amino group of this guanine with C7 adopting the R configuration. This model is consistent with the experimental evidence on the DNA binding of these drugs. An alternative binding mode based on opening of the oxazolidine ring and alkylation at C3a also was feasible according to molecular mechanics calculations. The geometry of naphthyridinomycin does not permit interstrand cross-linking involving both C3a and C7, but formation of a cross-link to protein appears possible. When the covalent naphthyridinomycin-d(ATGCAT)2 models were refined in the presence of water and counterions, the models with the most favorable net binding enthalpies were the same as those produced by simulation in vacuum. Qualitative estimates of the relative entropy changes resulting from adduct formation were based on the number of ordered (hydrogen bonded) water molecules released from d(ATGCAT)2 and from the drug. In all cases but one, d(ATGCAT)2 loses five water molecules. It loses six in the C3a covalent model with 5',S geometry. Naphthyridinomycin hydroquinone loses up to two water molecules, depending on the particular adduct. The 3',R model was again favored for the C7 covalent adduct. Among the C3a covalent models, the one with 5',R geometry lost the second most water molecules, but it had the best binding enthalpy.

Topics: Alkylation; Anti-Bacterial Agents; Base Sequence; Binding, Competitive; Chemical Phenomena; Chemistry; Computer Simulation; DNA; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Sequence Data; Naphthyridines; Oligoribonucleotides; Stereoisomerism; Structure-Activity Relationship

Topics: Anti-Bacterial Agents; Naphthyridines