Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant therapeutic agents. Thus, hypoxia and extracellular acidosis are known to select for the most aggressive and resilient phenotypes and build poorly responsive regions of the tumor mass. Carbonic anhydrase (CA, EC 4.2.1.1) IX isoform is a surficial zinc metalloenzyme that is proven to play a central role in regulating intra and extracellular pH, as well as modulating invasion and metastasis processes. With its strong association and distribution in various tumor tissues and well-known druggability, this protein holds great promise as a target to pharmacologically interfere with the tumor microenvironment by using drug combination regimens. In the present review, we summarized recent publications revealing the potential of CA IX inhibitors to intensify cancer chemotherapy and overcome drug resistance in preclinical settings.

Bis-ADC complexes cis-[Pd{C(NHC₆H₄NH₂)N(H)R}₂]Cl₂ (R = Xyl 4a, Cy 4b, C₆H₄-4-F 4c) and cis-[Pt{C(NHC₆H₄NH₂)N(H)R}₂]Cl₂ (R = Xyl 5a, Cy 5b, C₆H₄-4-F 5c) were synthesized via the metal-mediated coupling of two isocyanide ligands in cis-[MCl₂(CNR)₂] (M = Pd, Pt; R = Xyl, Cy, C₆H₄-4-F) and 1,2-diaminobenzene. New compounds 4c and 5a–c were characterized by HR ESI⁺-MS, IR, and ¹H, ¹³C{¹H} and ¹⁹⁵Pt{¹H} NMR spectroscopy; the structures of 4a and 5a were elucidated by single-crystal X-ray diffraction. The stability of the ADC complexes in aqueous media (5 mM NaCl) was monitored by UV absorption spectroscopy, HR ESI⁺ mass spectrometry, and ¹⁹⁵Pt{¹H} NMR spectroscopy (for 5a). Molar conductivity measurements in MeOH (Λ_M = 167–173 Ω⁻¹ mol⁻¹ cm²) indicate that, in this solvent, the ADC complexes exist as dicationic species of [A][Q]₂ type. The ADC complexes binding to CT DNA was investigated by means of spectroscopic and hydrodynamic techniques including UV absorption and circular dichroism spectroscopy, fluorescence spectroscopy, low-gradient viscometry, flow birefringence, and AFM imaging. As a result, complexes 4a and 5a were shown to bind double-stranded DNA predominantly via the formation of monofunctional adducts in the major groove of the macromolecule. Binding of the ADC complexes also provokes the formation of a large number of intermolecular DNA–DNA contacts in solution. The antiproliferative activity of all prepared ADC complexes 4a–c and 5a–c was evaluated in vitro against three human carcinoma cell lines (HT-29, MDA-MB-231, and MCF-7) and two non-tumorigenic cell lines (L929 and RC-124) and compared to that of cisplatin. Among the compounds studied, complexes 4a and 5a appeared to be the most active species with IC₅₀ values in MCF-7 cells of about 10 μM.

The enzyme NRH:quinone oxidoreductase 2 (NQO2) plays an important role in the pathogenesis of various diseases such as neurodegenerative disorders, malaria, glaucoma, COVID-19 and cancer. NQO2 expression is known to be increased in some cancer cell lines. Since 3-arylidene-2-oxindoles are widely used in the design of new anticancer drugs, such as kinase inhibitors, it was interesting to study whether such structures have additional activity towards NQO2. Herein, we report the synthesis and study of 3-arylidene-2-oxindoles as novel NRH:quinone oxidoreductase inhibitors. It was demonstrated that oxindoles with 6-membered aryls in the arylidene moiety were obtained predominantly as E-isomers while for some 5-membered aryls, the Z-isomers prevailed. The most active compounds inhibited NQO2 with an IC₅₀ of 0.368 µM. The presence of a double bond in the oxindoles was crucial for NQO2 inhibition activity. There was no correlation between NQO2 inhibition activity of the synthesized compounds and their cytotoxic effect on the A549 cell line.