Photopharmacology is actively developing and bringing new opportunities for the design of chemotherapy drugs. Several photoswitchable active compounds have been developed to inhibit microtubules in cancers. Analogues of combretastatin A-4 (CA4) are the most promising representatives of α-tubulin inhibitors. It is now clear that monotherapy with such photoswitchable agents has very limited applications in oncology. Aim of the study: to discover effective combinations of CA4 analogues with chemotherapy drugs and metformin.
The MTT test was used to evaluate A431 cell viability. Analogs of combretastatin A-4 based on quinazoline stilbenes were obtained by an alternative method - the Wittig reaction by condensation of the corresponding aldehydes with quinazoline phosphorus ylides in good yields (65-80%). The latter were synthesized by the reaction of quinazoline chloromethyl derivatives with triethyl phosphite. All quinazoline analogs of CA-4 were obtained in the e-form, which is confirmed by the constant of the spin-spin bond of olefinic protons (15.8-16.2 Hz).
Screening of new CA4 analogues showed that hit compounds can reduce the viability of A431 cells with IC50 values below 10 μM. Irradiation of hit compound ma-6595 ((E) -2- (3,4,5-trimethoxystyryl) quinazolin-4 (3H) -one) at λ=365 nm resulted in isomerization giving Z-isomer (ratio of E and Z isomers was 1.25:1); irradiation of ma-6595 caused an increase in antiproliferative activity by 5.4 times. Several effective combinations of ma-6595 photoproduct with chemotherapy drugs have been identified. ma-6595 photoproduct enhanced the effect of cisplatin and 5-fluorouracil on A431 cells. The strongest synergistic effect on cell viability was found for the combination of 5 mM metformin with 1 μM ma-6595 photoproduct (combination index <1).
A new highly active series of CA4 analogues have been provided. The hit compound enhanced the effect of cisplatin and 5-fluorouracil on epidermoid carcinoma cells. Moreover, the combination of the CA4 analogue with the cancer cell metabolism inhibitor metformin was very effective. Novel analogues of CA4 can be used to develop combination therapies and to reduce the dosage of chemotherapy drugs.
The authors.
The Russian Science Foundation (project 18-13-00308, chemistry) and Minobrnauki of Russia (project 075-15-2020-789, experiments with cisplatin).
All authors have declared no conflicts of interest.