The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.
This report details the invention of a method to enable syntheses of psychotrimine, 1, and the kapakahines F and B, 2 & 3, on a gram scale and in a minimum number of steps. Mechanistic inquiries are presented for the key enabling quaternization of indole at the C3 position by electrophilic attack of an activated aniline species. Excellent chemo-, regio-, and diastereoselectivities are observed for reactions with o-iodoaniline, an indole cation equivalent. Additionally, the scope of this reaction is broad with respect to the tryptamine and aniline components. The anti-cancer profiles of psychotrimine, 1, and kapakahines F and B, 2 & 3, have also been evaluated.
The syntheses of a bis indole and an indole salicylate with the required axial chirality for diazonamide A are reported. Atropselectivity in these biaryl systems is enforced by an sp(3) stereogenic center in a lactone tether in both cases. [structure: see text]
The putative reductive activation chemistry of the diazoparaquinone antibiotics was modeled with Bu(3)Sn-H and prekinamycin dimethyl ether along with prekinamycin itself. Reaction in various combinations of aromatic solvents, with and without the nucleophile benzylmercaptan present, led to isolation of both radical-trapping arene adducts and nucleophilic capture benzyl thioether products. On the basis of these product distribution studies, the intermediacies of, first, a cyclopentenyl radical and, next, an orthoquinonemethide electrophile are postulated.
The diazoparaquinone family of antibiotics, exemplified by the naturally occurring species prekinamycin (1a), 1 kinamycin F (2), 2 and lomaiviticin A (3), 3 has had a long and storied history, featuring two major structural revisions (N-cyanocarbazole → diazofluorene for the kinamycins, 4 and diazobenzo [b]fluorene → diazobenz[a]-fluorene for isoprekinamycin (not shown) 5 ). Following these corrections, two mechanism-of-action hypotheses have been proposed. Jebaratnam, using diazofluorene as a model system, suggested that oxidative activation of the diazo function might lead to DNA damaging reactive oxygen species via a putative C(11) radical. 6 Dmitrienko, employing the isoprekinamycin structure as a probe molecule, favored an alternative mechanism whereby enhanced diazonium character of the N 2 group as a consequence of an internal hydrogen bond network provided a site for nucleophilic attack by DNA amino groups, possibly leading to DNA damaging C(11) radicals as well. 7 A disclosure by He et al. on the structure and biological activity of lomaiviticin A (3) attributed its profound cytotoxicity (IC 50 's of 0.7-6.0 nM for a variety of tumor cell lines) 3 to double-stranded DNA cleavage under reducing conditions.Correspondence to: Ken S. Feldman, ksf@chem.psu.edu. Supporting Information Available: Experimental procedures and characterization data for 10a-e and 11a-g. This material is available free of charge via the Internet at http://pubs.acs.org. Neither Jebaratnam nor Dmitrienko utilized a diazoparaquinone-containing species for their studies, and an alternative mechanism-of-action that directly incorporates both this specific functionality and the reductive activation observation of He can be envisioned (Scheme 1). This proposal does not stray far from orthodox and precedented mechanisms of known paraquinoid antitumor agents, such as mitomycin and the anthracyclins. 8 The observation that lomaiviticin A operates through bioreductive activation is suggestive of one-electron addition to the quinone of generic diazoparaquinone 4 to give a reactive semiquinone 5 following protonation (not obligatory). The radical 5 so generated can be represented by the resonance form 6. This pivotal radical (or radical anion) 5/6 can furnish the second key intermediate of this hypothesis, a C(11) radical 7, provided that C(11) is pyramidalized sufficiently to permit adequate overlap between the enol (enolate) orbitals and σ* C-N for rapid loss of N 2 . If this sequence occurs in proximity to DNA, then H-atom abstraction seems plausible by analogy with the similar reaction of a related indenyl monoradical derived from neocarzinostatin and p-hydroxythiophenol, 9 and the hydroxymethylacylfulvene-containing intermediate 8 along with a DNA radical will be formed. At this point in the mechanistic speculation, there are two distinct avenues by which these two species, 8 and DNA • , might react further to lead to the observed result with lomaiviticin A. Generation of a DNA-based radical (C(4′), C(5′), or C(1′)) itself may be sufficien...
Iterative structure-activity analyses in a class of highly functionalized furo[2,3-]pyridines led to the identification of the second generation pan-genotypic hepatitis C virus NS5B polymerase primer grip inhibitor BMT-052 (), a potential clinical candidate. The key challenge of poor metabolic stability was overcome by strategic incorporation of deuterium at potential metabolic soft spots. The preclinical profile and status of BMT-052 () is described.
The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 () as a preclinical candidate.
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