Abstract：OBJECTIVE To design and synthesize a novel set of 20 stilbenenitrile sulfonamide derivatives based on combretastatin A-4 (CA-4) and ABT-751 possessing high potency and low toxicity. METHODS The anti-proliferation activity and toxicity of these compounds were evaluated by MTT assay with five kinds of cancer cell lines and two normal cell lines, and the candidates were selected out. Then the cell cycle and apoptosis assays were carried out and the effect of the candidate on the expressions of VEGF and MMP-9 were evalusted. RESULTS A majority of compounds demonstrated potent anti-proliferation activity in five kinds of tumor cell lines. Particularly, the compound 8h exhibited the most potent anticancer activity in MCF-7 cancer cell line (IC50=8.7 μmol·L-1), but low toxicity on normal human breast cell MCF-10A (IC50>100 μmol·L-1), which showed a selectivity. Simultaneously, compound 8h inhibited the proliferation of MCF-7 by arresting at the G2/M phase. In addition, the inhibition of VEGF expression of compound 8h was concentration-dependent under hypoxia and normoxia and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. Synchronously, the inhibition of MMP-9 expression of compound 8h was concentration-dependent and the inhibition effect was superior than CA-4′s and taxol′s at the same concentration. CONCLUSION Compound 8h are worthy of further study as an efficient and low-toxicity anti-breast cancer drug.
SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[2]
DAGENAIS G R, LEONG D P, RANGARAJAN S, et al. Variations in common diseases, hospital admissions, and deaths in middle-aged adults in 21 countries from five continents (PURE):A prospective cohort study[J]. Lancet, 2020, 395(10226):785-794.
[3]
HAMZE A, ALAMI M, PROVOT O. Developments of iso Combretastatin A-4 derivatives as highly cytotoxic agents[J]. Eur J Med Chem, 2020, 190:112110. Doi: 10.1016/j.ejmech.2020.112110.
[4]
XIA L Y, ZHANG Y L, YANG R, et al. Tubulin inhibitors binding to colchicine-site: a review from 2015 to 2019[J]. Curr Med Chem, 2020, 27(40):6787-6814.
[5]
NAGAIAH G, REMICK S C. Combretastatin A4 phosphate: a novel vascular disrupting agent[J]. Future Oncol, 2010, 6(8):1219-1228.
[6]
LI Y T, WANG J H, PAN CW, et al. Syntheses and biological evaluation of 1,2,3-triazole and 1,3,4-oxadiazole derivatives of imatinib[J]. Bioorg Med Chem Lett, 2016, 26(5):1419-1427.
[7]
LI J J, MA J, XIN Y B, et al. Synthesis and pharmacological evaluation of 2,3-diphenyl acrylonitriles-bearing halogen as selective anticancer agents[J]. Chem Biol Drug Des, 2018, 92(2):1419-1428.
[8]
SCOTT K A, NJARDARSON J T. Analysis of US FDA-approved drugs containing sulfur atoms[J]. Top Curr Chem (Cham), 2018, 376(1):5. Doi: 10.1007/s41061-018-0184-5.
[9]
YANG J Q, LEI Y Y, YANG H, et al. Synthesis and bioactivity of novel phosphonate derivatives containing thiophene and sulfonamide group[J]. Chin Pharm J(中国药学杂志), 2019, 54(24):2055-2059.
[10]
ABDEL-MAKSOUD M S, EL-GAMAL M I, LEE B S, et al. Discovery of new imidazo[2,1-b]thiazole derivatives as potent Pan-RAF inhibitors with promising in vitro and in vivo anti-melanoma activity[J]. J Med Chem, 2021, 64(10):6877-6901.
[11]
FOX E, MOSSE Y P, MEANY H M, et al. Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children′s oncology group (ANBL0621)[J]. Pediatr Blood Cancer, 2014, 61(6):990-996.
[12]
WANG Y T, CAI X C, SHI T Q, et al. Synthesis, molecular docking and biological evaluation of 1-phenylsulphonyl-2-(1-methylindol-3-yl)-benzimidazole derivatives as novel potential tubulin assembling inhibitors[J]. Chem Biol Drug Des, 2017, 90(1):112-118.
[13]
LI X Y, ZHANG T J, KAMARA M O, et al. Discovery of N-phenyl-(2,4-dihydroxypyrimidine-5-sulfonamido)phenylurea-based thymidylate synthase (TS) inhibitor as a novel multi-effects antitumor drugs with minimal toxicity[J]. Cell Death Dis, 2019, 10(7):532. Doi: 10.1038/s41419-019-1773-0.
[14]
NUTI E, CANTELMO A R, GALLO C, et al. N-O-Isopropyl sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors: hit selection and in vivo antiangiogenic activity[J]. J Med Chem, 2015, 58(18):7224-7240.
[15]
DAS S, AMIN S A, JHA T. Insight into the structural requirement of aryl sulphonamide based gelatinases (MMP-2 and MMP-9) inhibitors-Part I: 2D-QSAR, 3D-QSAR topomer CoMFA and Naïve Bayes studies-First report of 3D-QSAR Topomer CoMFA analysis for MMP-9 inhibitors and jointly inhibitors of gelatinases together[J]. SAR QSAR Environ Res, 2021, 32(8):655-687.
[16]
XIN Y B, LI J J, ZHANG H J, et al. Synthesis and characterisation of (Z)-styrylbenzene derivatives as potential selective anticancer agents[J]. J EnzymInhib Med Chem, 2018, 33(1):1554-1564.
[17]
BARD B, MARTEL S, CARRUPT P A. High throughput UV method for the estimation of thermodynamic solubility and the determination of the solubility in biorelevant media[J]. Eur J Pharm Sci, 2008, 33(3):230-240.
[18]
AN H, LEE S, LEE J M, et al. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-truncation strategy[J]. J Med Chem, 2018, 61(20):9266-9286.
[19]
WARD M P, SPIERS J P. Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion[J]. Br J Pharmacol, 2017, 174(10):1116-1130.
[20]
JIANG H, LI J. Priliminary study on the dissolution improvement mechanism of Neohesperidin on Naringin in water solution[J]. Chin Pharm J(中国药学杂志), 2021, 56(6):484-488.
[21]
CORREA DE SAMPAIO P, AUSLAENDER D, KRUBASIK D, et al. A heterogeneous in vitro three dimensional model of tumour-stroma interactions regulating sprouting angiogenesis[J]. PLoS One, 2012, 7(2):e30753. Doi: 10.1371/journal.pone.0030753.
2023, Vol. 58 
