Synthesis of Several Cytisine Derivatives and their Cytotoxicities against A431, A375, and HCT 116 Tumor Cell Lines
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SYNTHESIS OF SEVERAL CYTISINE DERIVATIVES AND THEIR CYTOTOXICITIES AGAINST A431, A375, AND HCT 116 TUMOR CELL LINES
P. R. Petrova,1 A. V. Koval′skaya,1 I. P. Tsypysheva,1* and A. S. Bunev2
Cytotoxicities of the quinolizidine alkaloid (–)-cytisine and 19 of its derivatives with substituents in the 3-, 9-, and 11-positions were assessed against A431 (epidermal carcinoma), A375 (melanoma), and HCT 116 (colorectal carcinoma) tumor cell lines using the MTT assay (etoposide reference drug). Practically all synthesized compounds at a concentration of 30 μM possessed slight ability to inhibit metabolic activity of these cell lines except benzylcytisine 4, methylcytisines 18 and 19, which contained a phenylurea fragment in the 9- or 11-position of the 2-pyridone core, and 11-chloro adamantylthiocarboxamide 16. Thiocarboxamide 16 reduced A431 cell survival up to 56.06% under the experimental conditions; derivatives 4, 18, and 19, of HCT 116 cell line by 57.52, 58.84, and 56.34%, respectively. Keywords: (–)-cytisine, methylcytisine, cytotoxicity, A431, A375, HCT 116. Natural compounds are traditionally used to treat a variety of diseases. Their separate classes have emerged as platforms of choice for designing new drugs. According to statistics, >25% of drugs approved for clinical use are derivatives of secondary plant, animal, and marine-organism metabolites, among which almost 49% are cancer chemotherapeutic agents [1]. This is understandable because natural compounds, primarily alkaloids, have a long history of use to treat oncological diseases and the most effective antitumor agents were designed based on them [2, 3]. Cytotoxicities of derivatives of the quinolizidine alkaloid (–)-cytisine (1) and methylcytisine (2) with thiocarboxamide, carboxamide, thiourea, and urea fragments (these pharmacophores are often incorporated into molecules of known cancer chemotherapeutic agents [6, 7]), i.e., compounds 3, 4, and 8–23, were assessed considering the recently discovered potent cytotoxicity of conjugates of 1 with 1,3-dimethyluracil and ferrocene against A549 (lung carcinoma), MCF7 (breast cancer), Jurkat (lymphoblastic leukemia), and SH-SY5Y (neuroblastoma) tumor cell lines [4, 5]. R3 N
N
N
R1
O
O
R2
N H
6
N H
N
O
N N
O 1 - 12, 14 - 23
O 13
1: R1 = R2 = R3 = H; 2: R1 = R2 = H, R3 = Me; 3: R1 = R2 = H, R3 = All; 4: R1 = R2 = H, R3 = Bn; 5: R1 = R3 = H, R2 = Cl 6: R1 = NH2, R2 = H, R3 = Me; 7: R1 = NCS, R2 = H, R3 = Me; 8: R1 = R2 = H, R3 = (CO)NH2; 9: R1 = R2 = H, R3 = (CO)NHAll 10: R1 = R2 = H, R3 = (CO)NHPh; 11: R1 = R2 = H, R3 = (CO)NHAd; 12: R1 = R2 = H, R3 = (CO)NH(CH2)2OH 14: R1 = R2 = H, R3 = (CS)NH2; 15: R1 = R2 = H, R3 = (CS)NHPh; 16: R1 = H, R2 = Cl, R3 = (CS)NHAd 17: R1 = R2 = H, R3 = (CS)NH(CO)Ph; 18: R1 = NH(CO)NHPh, R2 = H, R3 = Me 19: R1 = H, R2 = NH(CO)NHPh, R3 = Me 20: R1 = NH(CS)NHAll, R2 = H, R3 = Me; 21: R1 = NH(CS)NHPh, R2 = H, R3 = Me; 22: R1 = NH(CS)NH(CH2)2NH2, R2 = H, R3 = Me 23: R1 = NH(CS)NH(Et)2, R2 = H, R3 = Me
1) Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Ac
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