New approach of delivering cytotoxic drugs towards CAIX expressing cells : A concept of dual-target drugs

Abstract Carbonic anhydrase IX (CAIX) is a hypoxia-regulated and tumor-specific protein that maintains the pH balance of cells. Targeting CAIX might be a valuable approach for specific delivery of cytotoxic drugs, thereby reducing normal tissue side-effects. A series of dual-target compounds were designed and synthesized incorporating a sulfonamide, sulfamide, or sulfamate moiety combined with several different anti-cancer drugs, including the chemotherapeutic agents chlorambucil, tirapazamine, and temozolomide, two Ataxia Telangiectasia and Rad3-related protein inhibitors (ATRi), and the anti-diabetic biguanide agent phenformin. An ATRi derivative (12) was the only compound to show a preferred efficacy in CAIX overexpressing cells versus cells without CAIX expression when combined with radiation. Its efficacy might however not solely depend on binding to CAIX, since all described compounds generally display low activity as carbonic anhydrase inhibitors. The hypothesis that dual-target compounds specifically target CAIX expressing tumor cells was therefore not confirmed. Even though dual-target compounds remain an interesting approach, alternative options should also be investigated as novel treatment strategies

Electronic Spectra of (MCO)6 (M = Cr,Mo,W) Revisited by a Relativistic TDDFT Approach.

Relativistic time dependent density functional calculations have been performed on the excited states of the M(CO)6 (M = Cr, Mo, W) series. Our results, in agreement with previous density functional1 and ab initio2 calculations on Cr(CO)6, indicate that in all members of the series the lowest excited states in the spectra do not correspond to ligand field (LF) excitations, as has been accepted in the past. Instead they correspond to charge transfer (CT) states. The LF excitations are calculated at much higher energy than suggested by the original assignment by Beach and Gray3 and at different energy along the M(CO)6 series, being much higher in the heavier carbonyls than in Cr(CO)6. These results lead to a definitive reassessment of the role of the LF states in the photochemical dissociation of the metal−CO bonds in the M(CO)6 series, suggesting that the experimentally observed photodissociation of the M−CO bond upon irradiation into the lowest energy bands occurs in the heavier carbonyls, as it does in Cr(CO)6, from CT and not from LF states. A comparison with the experimental data available and, in the case of Cr(CO)6, also with high-level correlated ab initio calculations2 proves the reliability of the present TDDFT approach. The choice of the exchange−correlation (XC) functional is found to have a large effect on the excitation energies, demonstrating that even for quite “normal”, low-lying excitations the XC functional may play an important role. In the heavier carbonyls, mostly in W(CO)6, relativistic effects are seen to be relevant for the LF states as well as for the CT states arising from the (2t2g)5(3t2g)1 configuration