Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors
Abstract
:1. Introduction
2. Results and Discussion
2.1. Drug Design and Chemistry
2.2. Biological Assessments
In Vitro Carbonic Anhydrase Inhibition
- For compounds lacking linkers, almost no difference in activities can be found for non-cyclic (13) and bicyclic (16) thioureas.
- The insertion of a linker between the carbohydrate and the coumarin residues of byclicic structures proved to be benefitial for the inhibition of both membrane-bound enzymes (16 vs. 24a–c).
- The presence of a Ph residue on C-3 both in linear thioureas (21e,f) and imidazolidine-2-thiones (24d,e) provoked an impariment of the inhibitory profile against CA IX and XII, reaching the submicromolar range. This is probably due to steric clash within the active site.
- Considering the effect of the substituents (n = 4), the observed order of activity is:
- CA IX: R1 = Me, R2 = Cl (24h) > R1 = Me, R2 = H (24b) > R1 = Ph, R2 = H (24e). Indeed, compound 24h provided the strongest CA IX inhibitor of the series (Ki = 6.8 nM), roughly 3.8-fold stronger than AAZ.
- CA XII: R1 = Me, R2 = H (24b) > R1 = Me, R2 = Cl (24h) > R1 = Ph, R2 = H (24e).
- The best template for the inhibition of CA XII was proved to be a short linkage (n = 3), and the monosubtitution of coumarin on C-3 with small substituents (Me, 24a), with Ki = 10.1 nM
- Little differences in activity were found by changing the carbohydrate configuration (24c vs. 26).
2.3. Antiproliferative Activities
2.4. Docking Simulations
3. Materials and Methods
3.1. Chemistry
3.1.1. General Methods
3.1.2. General Procedure for the Preparation of Imidazolidine-2-Thiones 8a–c, 9a,b
3.1.3. N-(Methyl 2-deoxy-α-d-Glucopyranosid-2-yl)-N′-(4-methyl-2′-oxo-2′H-chromen-7′-yl)thiourea (13)
3.1.4. 1-(4′-Methyl-2′-oxo-2′H-chromen-7′-yl)-(1″,2″-dideoxy-α-d-glucofurano)[2,1-d]imidazolidine-2-thione (16)
3.1.5. General Procedure for the Preparation of 7-Hidroxycoumarins via Pechmann Condensation
3.1.6. General Procedure for the O-Alkylation of 7-Hydroxycoumarins with α,ω-Dibromoalkanes (17a–i)
3.1.7. General Procedure for the Preparation of Azides 18a–i
3.1.8. General Procedure for the Preparation of Amines 19a–i
3.1.9. General Procedure for the Preparation of Isothiocyanates 20a–i
3.1.10. General Procedure for the Preparation of Coumarin-Derived Glycol-Thioureas 21e,f
3.1.11. General Procedure for the Preparation of Coumarin-Derived Imidazolidine-2-Thiones 24a–i, 26
3.2. CA Inhibition Assays
3.3. Antiproliferative Assays
3.4. Docking Simulations
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Ki (nM) | S.I. b | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
hCA I | hCA II | hCA IV | hCA IX | hCA XII | I/IX | I/XII | II/IX | II/XII | ||
d-Gluco | 8a (n = 0, R = p-SO2NH2) | 765.5 | 60.0 | 347.6 | 175.0 | 502.5 | 4.4 | 1.5 | 0.3 | 0.1 |
8b (n = 0, R = m-SO2NH2) | 4578 | 5053 | 45.1 | 252.6 | 216.0 | 18.1 | 21.2 | 20.0 | 23.4 | |
8c (n = 2, R = p-SO2NH2) | 84.7 | 8.9 d | 1050 | 61.4 | 51.4 | 1.4 | 1.6 | 0.1 | 0.1 | |
d-Galacto | 9a (n = 0, R = p-SO2NH2) | 90.3 | 116.0 | 4572 | 5657 | 2.9 | 0.02 | 31.1 | 0.02 | 40.0 |
9b (n = 0, R = m-SO2NH2) | 7807 | 927.6 | 27,250 | 9627 | 5.1 | 0.8 | 1531 | 0.1 | 181.9 | |
1a [26] | 7680 | 7.0 | --- c | 282 | 8.2 | 27.2 | 937 | 0.02 | 0.9 | |
1c [26] | 9.0 | 108 | --- | 8.7 | 9.7 | 1.0 | 0.9 | 12.4 | 11.1 | |
2a [26] | 6840 | 222 | --- | 7.0 | 20.1 | 977.1 | 340 | 31.7 | 11.0 | |
2c [26] | 5790 | 9.3 | --- | 2.8 | 10.2 | 2067.9 | 568 | 3.3 | 0.9 | |
3a [27] | 2700 | 9700 | --- | 77 | 7.9 | 35.1 | 342 | 126 | 1228 | |
3b [27] | 100 | 8600 | --- | 9.0 | 207 | 11.1 | 0.5 | 956 | 41.5 | |
4a [27] | 3600 | 7700 | --- | 74 | 104 | 48.6 | 34.6 | 104 | 74.0 | |
4b [27] | 4300 | 940 | --- | 42 | 14 | 102.4 | 307.1 | 22.4 | 67.1 | |
AAZ | 250 | 12.1 | 74.0 | 25.8 | 5.7 | 9.7 | 43.9 | 0.5 | 2.1 |
Compound | Ki (nM) | S.I. b | ||||||
---|---|---|---|---|---|---|---|---|
hCA I | hCA II | hCA IX | hCA XII | I/IX | I/XII | II/IX | II/XII | |
>100,000 | >100,000 | 73.9 | 56.1 | >1353 | >1783 | >1353 | >1783 | |
>100,000 | >100,000 | 89.1 | 91.0 | >1122 | >1099 | >1122 | >1099 | |
>100,000 | >100,000 | 105.8 | 227.8 | >945 | >439 | >945 | >439 | |
>100,000 | 17,300 | 116.5 | 163.9 | >858 | >610 | 148 | 106 | |
24a R1 = Me, R2 = H, n = 3 | >100,000 | >100,000 | 45.3 | 10.1 c | >2208 | >9901 | >2208 | >9901 |
24b R1 = Me, R2 = H, n = 4 | >100,000 | >100,000 | 70.7 | 25.7 | >1414 | >3891 | >1414 | >3891 |
24c R1 = Me, R2 = H, n = 6 | >100,000 | >100,000 | 22.4 | 72.1 | >4464 | >1387 | >4464 | >1387 |
24d R1 = Ph, R2 = H, n = 3 | >100,000 | >100,000 | 91.4 | 260.3 | >1094 | >384 | >1094 | >384 |
24e R1 = Ph, R2 = H, n = 4 | >100,000 | >100,000 | 177.3 | 140.4 | >564 | >712 | >564 | >712 |
24h R1 = Me, R2 = Cl, n = 4 | >100,000 | >100,000 | 6.8 | 37.5 | >14,706 | >2667 | >14,706 | >2667 |
>100,000 | >100,000 | 28.6 | 61.4 | >3947 | >1629 | >3947 | >1629 |
Compound | Drug-Sensitive Cell Lines | Multidrug-Resistant Cell Lines | ||||
---|---|---|---|---|---|---|
A549 (Lung, Non-Small) | HBL-100 (Breast) | HeLa (Cervix) | SW1573 (Lung, Non-Small) | T-47D (Breast) | WiDr (Colon) | |
79 ± 36 | 86 ± 25 | 83 ± 30 | 79 ± 37 | >100 | >100 | |
34 ± 4.0 | 23 ± 3.2 | 25 ± 8.0 | 9.7 a | 30 ± 7.4 | 36 ± 16 | |
64 ± 31 | 23 ± 0.8 | 31 ± 0.2 | 5.7 ± 1.8 | 70 ± 23 | 47 ± 11 |
Enzyme/Compound | 24h (Closed) | 24h (Open E) | 24h (Open Z) |
---|---|---|---|
hCA IX | −8.4781 | −10.1987 | −9.6243 |
hCA XII | −7.1633 | −9.3104 | −9.8885 |
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Martínez-Montiel, M.; Romero-Hernández, L.L.; Giovannuzzi, S.; Begines, P.; Puerta, A.; Ahuja-Casarín, A.I.; Fernandes, M.X.; Merino-Montiel, P.; Montiel-Smith, S.; Nocentini, A.; et al. Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors. Int. J. Mol. Sci. 2023, 24, 9401. https://doi.org/10.3390/ijms24119401
Martínez-Montiel M, Romero-Hernández LL, Giovannuzzi S, Begines P, Puerta A, Ahuja-Casarín AI, Fernandes MX, Merino-Montiel P, Montiel-Smith S, Nocentini A, et al. Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors. International Journal of Molecular Sciences. 2023; 24(11):9401. https://doi.org/10.3390/ijms24119401
Chicago/Turabian StyleMartínez-Montiel, Mónica, Laura L. Romero-Hernández, Simone Giovannuzzi, Paloma Begines, Adrián Puerta, Ana I. Ahuja-Casarín, Miguel X. Fernandes, Penélope Merino-Montiel, Sara Montiel-Smith, Alessio Nocentini, and et al. 2023. "Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors" International Journal of Molecular Sciences 24, no. 11: 9401. https://doi.org/10.3390/ijms24119401
APA StyleMartínez-Montiel, M., Romero-Hernández, L. L., Giovannuzzi, S., Begines, P., Puerta, A., Ahuja-Casarín, A. I., Fernandes, M. X., Merino-Montiel, P., Montiel-Smith, S., Nocentini, A., Padrón, J. M., Supuran, C. T., Fernández-Bolaños, J. G., & López, Ó. (2023). Conformationally Restricted Glycoconjugates Derived from Arylsulfonamides and Coumarins: New Families of Tumour-Associated Carbonic Anhydrase Inhibitors. International Journal of Molecular Sciences, 24(11), 9401. https://doi.org/10.3390/ijms24119401