Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents

In one aspect, the present disclosure provides new analogs of uncialamycin of formulae (I) and (II). The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates comprising the compounds of formulae (I) and (II)

Total synthesis of amphoteronolide B

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Total synthesis of amphoteronolide B and amphotericin B. 2. Total synthesis of amphoteronolide B

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Total synthesis of amphotericin B. 3. The final stages

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Involvement of Caspase Activation in Azaspiracid-Induced Neurotoxicity in Neocortical Neurons

Azaspiracids (AZAs) are a novel group of marine phycotoxins that have been associated with severe human intoxication. We found that AZA-1 exposure increased lactate dehydrogense (LDH) efflux in murine neocortical neurons. AZA-1 also produced nuclear condensation and stimulated caspase-3 activity with an half maximal effective concentration (EC50) value of 25.8nM. These data indicate that AZA-1 triggers neuronal death in neocortical neurons by both necrotic and apoptotic mechanisms. An evaluation of the structure-activity relationships of AZA analogs on LDH efflux and caspase-3 activation demonstrated that the full structure of AZAs was required to produce necrotic or apoptotic cell death. The similar potencies of AZA-1 to stimulate LDH efflux and caspase-3 activation and the parallel structure-activity relationships of azaspiracid analogs in the two assays are consistent with a common molecular target for both responses. To explore the molecular mechanism for AZA-1–induced neurotoxicity, we assessed the influence of AZA-1 on Ca2+ homeostasis. AZA-1 suppressed spontaneous Ca2+ oscillations (EC50 = 445nM) in neocortical neurons. A distinct structure-activity profile was found for inhibition of Ca2+ oscillations where both the full structure as well as analogs containing only the FGHI domain attached to a phenyl glycine methyl ester moiety were potent inhibitors. The molecular targets for inhibition of spontaneous Ca2+ oscillations and neurotoxicity may therefore differ. The caspase protease inhibitor Z-VAD-FMK produced a complete elimination of AZA-1–induced LDH efflux and nuclear condensation in neocortical neurons. Although the molecular target for AZA-induced neurotoxicity remains to be established, these results demonstrate that the observed neurotoxicity is dependent on a caspase signaling pathway

Total synthesis of amphoteronolide B and amphotericin B. 1. Strategy and stereocontrolled construction of key building blocks

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Stereocontrolled construction of key building blocks for the total synthesis of amphoteronolide B and amphotericin B

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