Ecofriendly synthesis of carbohydrate-derived heterocycles with potential antiproliferative activity Verónica Luque-Agudo, María Victoria Gil IACYS-Unidad de Química Verde y Desarrollo Sostenible, Departamento de Química Orgánica e Inorgánica, Universidad de Extremadura

“On water” methodology Introduction Energy efficiency Green Chemistry Atom economy Sustainability “On water” methodology Solventless reactions

Introduction Antimalarial Antibacterial Antifungal Anticancer

Introduction Antihypertensive Antifungal Anticoagulant Antitumor

Synthesis of 2-glyco-3-nitro-1,2-dihydroquinolines 1-3 days 59%-92% yield

Synthesis of 2-glyco-3-nitroquinolines 1-3 hours 47%-87% yield

Synthesis of 2-glyco-3-nitro-2H-chromenes 0.5-2.5 hours 40%-75% yield

Evaluation of their antiproliferative activity Breast (HBL-100) Cervix (HeLa) Non-small cell lung (A549) Non-small cell lung (SW1573) Breast (T-47D) Colon (WiDr)

GI50 Evaluation of their antiproliferative activity Compound concentration required to inhibit 50% cell growth Modified1 SRB protocol2 (NCI, USA) Cisplatin 5-fluorouracil Etoposide 1 P. Miranda, J.M. Padrón, J.I. Padrón, J. Villar, V.S. Martin, Chem. Med. Chem. 2006, 1, 323. 2 A. Monks, D. Scudiero, P. Skedan, R. Shoemaker, K. Paull, D. Vistica, C. Hose, J. Langley, P. Cronice, M. Vaigro-Wolf, M. Gary-Goodrich, H. Campbell, M. Mayo, J. Natl. Cancer Inst. 1991, 83, 757.

Evaluation of their antiproliferative activity: 1,2-DHQ’s

Evaluation of their antiproliferative activity: Q’s

Evaluation of their antiproliferative activity: chromenes

Evaluation of their antiproliferative activity: chromenes

Evaluation of their antiproliferative activity: chromenes

Conclusions New 2-glyco-3-nitro-1,2-DHQ’s, Q’s and 2H-chromenes have been synthesized by using green methodologies: catalysed solventless reactions In general, 1,2-DHQ’s and Q’s exhibit lower GI50 values than chemotherapeutic reference compounds, except in the cases of 3b, 6b, 13b and 13c against T-47D and WiDr cells Chromenes show a better antiproliferative profile against all cell lines than the three chemotherapeutic reference compounds, highlighting products 14, 11b and 11e

Acknowledgements

Ecofriendly synthesis of carbohydrate-derived heterocycles with potential antiproliferative activity Verónica Luque-Agudo, María Victoria Gil IACYS-Unidad de Química Verde y Desarrollo Sostenible, Departamento de Química Orgánica e Inorgánica, Universidad de Extremadura

Compound A549 HBL-100 HeLa SW1573 T-47D WiDr GI50 ± sD values(µM) 3a 29 ± 3.2 73 ± 29 33 ± 7.3 67 ± 26 71 ± 25 53 ± 16 6a 70 ± 28 72 ± 26 38 ± 6.9 72 ± 39 >100 90 ± 18 6a-deacet. 13a 56 ± 17 83 ± 23 43 ± 3.1 63 ± 9.7 54 ± 15 56 ± 16 3b 25 ± 9 26 ± 5.3 24 ± 8.3 40 ± 8.5 23 ± 5.6 30 ± 2.9 6b 37 ± 5 26 ± 6 90 ± 0.3 32 ± 0.38 47 ± 13 6b-deacet. 13b 15 ± 1.2 17 ± 0.91 16 ± 2.2 12 ± 2.4 18 ± 3.8 19 ± 3.4 3c 88 ± 17 97 ± 4.6 52 ± 2.3 91 ± 12 93 ± 12 82 ± 24 6c 89 ± 1.9 44 ± 8.1 41 ± 13 82 ± 17 59 ± 8.9 6c-deacet. 29 ± 4.4 32 ± 2.8 32 ± 6.4 54 ± 0.58 50 ± 9.8 49 ± 0.10 13c 31 ± 7.6 15 ± 2.5 28 ± 6.4 26 ± 3.7 Etoposide 0.7 ± 0.2 2.3 ± 0.9 3.0 ± 0.9 15 ± 1.5 22.0 ± 5.5 23.0 ± 2.1 5-fluorouracil Not tested 5.5 ± 2.3 15 ± 4.7 4.3 ± 1.6 47 ± 18 49 ± 6.7 Cisplatin 2.1 ± 0.6 1.9 ± 0.2 2.0 ± 0.3 3.0 ± 0.4 15.0 ± 2.3 26.0 ± 5.3

Compound A549 HBL-100 HeLa SW1573 T-47D WiDr GI50 ± sD values(µM) 9a 25 ± 8.3 39 ± 14 15 ± 6.2 35 ± 9.9 29 ± 7.7 32 ± 6.5 10a 9.2 ± 5.2 14 ± 4.3 14 ± 2.5 13 ± 2.9 16 ± 5.3 15 ± 3.2 9b 2.5 ± 0.86 2.9 ± 0.25 2.8 ± 0.40 2.4 ± 0.39 3.4 ± 0.19 1.9 ± 0.76 9c 3.0 ± 0.34 2.3 ± 0.055 2.8 ± 0.18 2.4 ± 0.34 3.5 ± 0.013 1.7 ± 0.39 9d 1.3 ± 0.38 2.0 ± 0.41 1.8 ± 0.69 1.0 ± 0.027 2.0 ± 0.53 2.6 ± 0.54 9d-deacet. 63 ± 32 32 ± 3.0 28 ± 3.3 20 ± 0.93 43 ± 11 66 ± 30 9e 7.7 ± 2.4 11 ± 4.4 7.0 ± 0.60 4.3 ± 2.0 16 ± 2.9 21 ± 4.5 9e-deacet. <100 14 2.2 ± 0.89 3.4 ± 0.45 2.1 ± 0.96 2.0 ± 0.89 3.4 ± 0.98 2.3 ± 1.3 15 39 ± 15 61 ± 16 42 ± 9.8 23 ± 3.2 9b+10b 2.2 ± 0.69 2.7 ± 0.47 2.0 ± 0.80 3.2 ± 0.55 4.1 ± 0.87 9c+10c 1.5 ± 0.28 1.8 ± 0.23 1.5 ± 0.55 0.96 ± 0.064 2.3 ± 0.85 2.7 ± 0.90 9d+10d 1.5 ± 0.72 1.9 ± 0.51 1.5 ± 0.38 1.3 ± 0.57 2.1 ± 0.68 2.4 ± 0.77 12a 32 ± 8.4 60 ± 28 26 ± 4.3 55 ± 16 32 ± 4.1 56 ± 13 11a 23 ± 4.3 27 ± 5.6 23 ± 4.1 23 ± 6.6 28 ± 4.3 11b 1.2 ± 0.19 2.0 ± 1.1 1.5 ± 0.20 1.2 ± 0.25 2.4 ± 0.71 3.1 ± 0.37 11e 2.4 ± 0.69 6.6 ± 3.1 2.7 ± 0.68 2.2 ± 0.29 5.2 ± 2.1 12 ± 1.6 16 22 ± 9.7 32 ± 3.7 24 ± 1.5 20 ± 2.8 18 ± 9.9 65 ± 21 17 58 ± 34 69 ± 7.6 44 ± 12 Etoposide 0.7 ± 0.2 2.3 ± 0.9 3.0 ± 0.9 15 ± 1.5 22.0 ± 5.5 23.0 ± 2.1 5-fluorouracil Not tested 5.5 ± 2.3 15 ± 4.7 4.3 ± 1.6 47 ± 18 49 ± 6.7 Cisplatin 2.1 ± 0.6 1.9 ± 0.2 2.0 ± 0.3 3.0 ± 0.4 15.0 ± 2.3 26.0 ± 5.3