- Platinum-Triggered Bond-Cleavage of Pentynoyl Amide and N-Propargyl Handles for Drug-Activation
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The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.
- Oliveira, Bruno L.,Stenton, Benjamin J.,Unnikrishnan,De Almeida, Cátia Rebelo,Conde, Jo?o,Negr?o, Magda,Schneider, Felipe S.S.,Cordeiro, Carlos,Ferreira, Miguel Godinho,Caramori, Giovanni F.,Domingos, Josiel B.,Fior, Rita,Bernardes, Gon?alo J. L.
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supporting information
p. 10869 - 10880
(2020/07/04)
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- A mild and selective method for N-dealkylation of tertiary amines
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Alkyl groups can be cleaved efficiently and selectively from tertiary alkyl amines using propargyl chloroformate. The propargyloxycarbonyl (Poc) protected secondary amines thus obtained can be deblocked under neutral and mild conditions using benzyltriethylammonium tetrathiomolybdate. The generality and compatibility of the method have been studied with a wide range of functionalities. Alkyl groups can be cleaved efficiently and selectively from tertiary alkyl amines using propargyl chloroformate. The propargyloxycarbonyl (Poc) protected secondary amines thus obtained can be deblocked under neutral and mild conditions using benzyltriethylammonium tetrathiomolybdate. The generality and compatibility of the method have been studied with a wide range of functionalities.
- Bhat, Ramakrishna G.,Ghosh, Yagnaseni,Chandrasekaran, Srinivasan
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p. 7983 - 7985
(2007/10/03)
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