Most multi‐action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for synthesis of PtIV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the PtIV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO2, rapidly generating the active drugs. In contrast, succinate‐linked drugs did not readily release the free drugs. The carbonate‐bridged ctc‐[Pt(NH3)2(PhB)(Gem‐Carb)Cl2] was significantly more cytotoxic than the succinate‐bridged ctc‐[Pt(NH3)2(PhB)(Gem‐Suc)Cl2], and more potent and less toxic than gemcitabine, cisplatin, and co‐administration of cisplatin and gemcitabine.
Multiaction Pt(IV) prodrugs can overcome resistance associated with the FDA approved Pt(II) drugs like cisplatin. Intracellular reduction of the octahedral Pt(IV) derivatives of cisplatin releases cisplatin and the two axial ligands. When the released axial ligands act synergistically with cisplatin to kill the cancer cells, we have multiaction prodrugs. Most Pt(IV) multiaction prodrugs have bioactive ligands possessing a carboxylate that is conjugated to the Pt(IV) because breaking the Pt(IV)−ligand bond releases the active moiety. As many drugs that act synergistically with cisplatin do not have carboxylates, a major challenge is to prepare multiaction Pt(IV) complexes with drugs that have amino groups or hydroxyl groups such that following reduction, the drugs are released in their active form. Our objective was to prepare multiaction Pt(IV) prodrugs that release bioactive molecules having amino groups. Because we cannot conjugate amino groups to the axial position of Pt(IV), we developed a novel and efficient approach for the synthesis of Pt(IV)−carbamato complexes and demonstrated that following reduction of the Pt(IV), the released carbamates undergo rapid decarboxylation, releasing the free amine, as in the case of the PARP-1 inhibitor 3aminobenzamide and the amino derivative of the HDAC inhibitor SAHA. Pt(IV)−carbamato complexes are stable in cell culture medium and are reduced by ascorbate. They are reduced slower than their carboxylato and carbonato analogues. We believe that this approach paves the way for preparing novel classes of multiaction Pt(IV) prodrugs with amino containing bioactive molecules that up to now were not accessible.
Metrics & MoreArticle Recommendations * sı Supporting Information ABSTRACT: "Multi-action" Pt(IV) derivatives of cisplatin with combretastatin A4 (CA4) bioactive ligands that are conjugated to Pt(IV) by carbonate are unique because the ligand (IC 50 < 10 nM) is dramatically 1000-folds more cytotoxic than cisplatin in vitro. The Pt(IV)-CA4 prodrugs were as cytotoxic as CA4 itself, indicating that the platinum moiety probably plays an insignificant role in triggering cytotoxicity, suggesting that the Pt(IV)-CA4 complexes act as prodrugs for CA4 rather than as true multi-action prodrugs. In vivo tests (Lewis lung carcinoma) show that ctc-[Pt(NH 3 ) 2 (PhB)(CA4)Cl 2 ] inhibited tumor growth by 93% compared to CA4 (67%), cisplatin (84%), and 1:1:1 cisplatin/CA4/PhB (85%) while displaying <5% body weight loss compared to cisplatin (20%) or CA4 (10%). In this case, and perhaps with other extremely potent bioactive ligands, platinum(IV) acts merely as a self-immolative carrier triggered by reduction in the cancer cell with only a minor contribution to cytotoxicity.
Dedicated to the late Prof.J .Katzhendler for his mentorship,inspiration and friendship.Abstract: Most multi-action Pt IV prodrugs have bioactive ligands containing carboxylates.T his is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. Am ajor challenge is to expand the arsenal of bioactive ligands to include those without carboxylates.W ed escribe ag eneral approach for synthesis of Pt IV prodrugs that release drugs with OH groups.W elinked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the Pt IV derivative of cisplatin by ac arbonate bridge.F ollowing reduction, the axial ligands lost CO 2 ,r apidly generating the active drugs.I n contrast, succinate-linked drugs did not readily release the free drugs.T he carbonate-bridged ctc-[Pt(NH 3 ) 2 (PhB)(Gem-Carb)Cl 2 ]w as significantly more cytotoxic than the succinate-bridged ctc-[Pt(NH 3 ) 2 (PhB)(Gem-Suc)Cl 2 ], and more potent and less toxic than gemcitabine,c isplatin, and coadministration of cisplatin and gemcitabine.
AuI‐carbene and PtIV−AuI‐carbene prodrugs display low to sub‐μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt‐derived PtIV(phenylbutyrate) complex to a AuI‐phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug PtIV(phenylbutyrate)‐AuI‐carbene (7) and the 1 : 1 : 1 co‐administration of cisPt: phenylbutyrate:2 efficiently inhibited tumor growth (≈95 %), much better than 2 (75 %) or cisPt (84 %), 7 exhibited only 5 % body weight loss compared to 14 % for 2, 20 % for cisPt and >30 % for the co‐administration. 7 was much more efficient than 2 at inhibiting TrxR activity in the isolated enzyme, in cells and in the tumor, even though it was much less efficient than 2 at binding to selenocysteine peptides modeling the active site of TrxR. Organ distribution and laser‐ablation (LA)‐ICP‐TOFMS imaging suggest that 7 arrives intact at the tumor and is activated there.
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