RESUMEN
Apoptolidinâ A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidinâ A consists of a 20-membered macrolide with mono- and disaccharide moieties. In contrast to apoptolidinâ A, the aglycone (apoptolidinone) shows no cytotoxicity (>10â µM) when evaluated against several tumor cell lines. Apoptolidinâ H, the C27 deglycosylated analogue of apoptolidinâ A, displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of apoptolidinsâ A and H with 5-azidopentanoic acid afforded azido-functionalized derivatives of potency equal to that of the parent macrolide. They also underwent strain-promoted alkyne-azido cycloaddition reactions to provide access to fluorescent and biotin-functionalized probes. Microscopy studies demonstrate apoptolidinsâ A and H localize in the mitochondria of H292 human lung carcinoma cells.
Asunto(s)
Antineoplásicos/química , Colorantes Fluorescentes/química , Macrólidos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Peroxidación de Lípido/efectos de los fármacos , Macrólidos/toxicidad , Microscopía Confocal , Pironas/química , Pironas/toxicidadRESUMEN
Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest.