Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Anticancer Activity
Panel | Cell Line | IGP [%] of Compound | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
11 | 12 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 24 | 25 | 26 | ||
Leukemia | CCRF-CEM | 1 | 4 | 27 | 30 | 7 | – | 2 | 11 | * | 85 | 27 | 19 | – |
K-562 | 6 | 67 | – | 45 | – | 7 | 12 | 70 | 20 | 95 | 42 | 72 | * | |
MOLT-4 | 7 | 21 | – | 27 | – | 6 | 5 | 18 | 9 | 85 | 9 | 20 | 8 | |
RPMI-8226 | * | * | – | 70 | – | * | 1 | 7 | * | 93 | 72 | 10 | * | |
SR | – | 15 | – | 16 | – | 12 | – | – | – | 95 | 1 | 29 | 19 | |
NSCLC | HOP-92 | * | * | – | 53 | – | * | * | 2 | * | 131 | 28 | * | – |
NCI-H522 | 7 | 25 | * | 43 | * | 8 | 9 | 19 | 5 | 110 | 28 | 12 | 8 | |
Colon cancer | HCC-2998 | 11 | 1 | * | 1 | * | * | 11 | 9 | 2 | 73 | * | 2 | * |
HCT-15 | * | 39 | 37 | * | 31 | 9 | * | 28 | * | 41 | * | 53 | 4 | |
KM12 | * | 43 | * | 25 | 4 | 7 | – | 24 | 14 | 89 | 27 | 49 | * | |
SW-620 | * | 24 | 30 | 10 | 21 | * | * | 30 | * | 82 | 12 | 40 | * | |
CNS cancer | SF-268 | * | 18 | 3 | 1 | 6 | * | * | 19 | 6 | 71 | * | 26 | * |
SF-295 | 11 | 13 | 6 | 43 | 13 | 10 | * | 10 | – | 147 | 48 | * | 1 | |
Melanoma | LOX IMVI | 7 | - | 59 | 10 | 56 | – | 3 | 47 | 4 | 96 | 10 | 59 | – |
MALME-3M | 9 | 1 | * | 58 | * | 3 | 6 | 6 | 5 | 101 | 44 | 2 | * | |
M14 | * | 17 | 16 | 27 | 17 | * | * | 9 | 0 | 77 | 25 | 29 | * | |
MDA-MB-435 | * | 9 | 16 | 11 | 12 | * | * | * | * | 93 | 15 | 23 | * | |
UACC-62 | * | 57 | 51 | 33 | 38 | * | * | 32 | * | 73 | 31 | 42 | 10 | |
Ovarian cancer | OVCAR-3 | * | * | * | 42 | * | * | * | * | * | 75 | 50 | * | * |
Renal cancer | A498 | 15 | 19 | 33 | 4 | 42 | 5 | 17 | 13 | 12 | 80 | 7 | 6 | 0 |
ACHN | * | 31 | 22 | 25 | 21 | * | * | 24 | * | 93 | 26 | 25 | * | |
CAKI-1 | 2 | 33 | 29 | * | 28 | 11 | * | 23 | * | 65 | 5 | 17 | 2 | |
UO-31 | 12 | 18 | 17 | 27 | 19 | 9 | 5 | 21 | 10 | 110 | 20 | 29 | 16 | |
Prostate cancer | PC-3 | 11 | 6 | 14 | 54 | 17 | * | 6 | 21 | 16 | 101 | 51 | 12 | * |
DU-145 | * | 16 | 5 | * | 7 | * | * | 18 | * | 67 | 1 | 32 | * | |
Breast cancer | MDA-MB-468 | * | 7 | – | 59 | – | 3 | * | * | * | 109 | 57 | * | * |
T-47D | 2 | 20 | 21 | 33 | 17 | 6 | 10 | 27 | 9 | 92 | 26 | 18 | 7 |
- (a)
- All compounds with 4-chlorophenylcarbamoyl (R2 = 4-Cl) moieties (12, 14, 16, 19, 21 and 25) are characterized by moderate to high activity with IGP range from 17 to 96% against the common cancer cell lines: leukemia (K-562, MOLT-4), colon cancer (HCT-15 and SW-620,) melanoma (LOX IMVI and UACC-62), and renal cancer (ACHN, CAKI-1) (Table 1), as well exhibit high overall activity with the average IGP for the whole panel in the range from 7 to 90%.
- (b)
- Apparently the introduction of a second chlorine atom in position 3 of the 4-chloro-phenylcarbamoyl moiety (R2 = 3,4-diCl) in compounds 17 and 26 definitely causes a loss of activity. In this case the highest IGP values of 12 and 19% are observed only for the leukemia SR cell line.
- (c)
- From among of the compounds with unsubstituted phenylcarbamoyl moieties (R2 = H; i.e., 11, 15, 18, 20 and 24) only compounds 15 and 24 exhibit high antiproliferative activity against certain cell lines: leukemia RPMI-8226 (IGP = 70 and 72%), NSCLC HOP-92 (IGP = 53 and 28%), CNS cancer (IGP = SF-295 43 and 48%), melanoma MALME-3M (IGP = 58 and 44%), ovarian cancer OVCAR-3 (IGP = 42 and 50%), prostate cancer PC-3 (IGP = 54 and 51%) or breast cancer MDA-MB-468 (IGP = 59 and 57%), respectively (Table 1). It should be noted that the mentioned cell lines, which are highly susceptible for compounds 15 and 24, do not exhibit significant sensitivity for their 4-chlorophenylurea (R2 = 4-Cl) analogs 16 and 25.
Panel | Cell line | 21 | Sulofenur b | ||||
---|---|---|---|---|---|---|---|
GI50 c | TGI d | LC50 e | GI50 c | TGI d | LC50 e | ||
Leukemia | CCRF-CEM | 8.2 | 43.6 | >100 | 29.8 | >100 | >100 |
K-562 | 3.0 | >100 | >100 | 10.2 | 77.1 | >100 | |
MOLT-4 | 19.9 | 68.1 | >100 | 26.4 | 98.2 | >100 | |
RPMI-8226 | 14.7 | 54.2 | >100 | 24.4 | 85.7 | >100 | |
SR | 11.8 | 51.6 | >100 | 57.0 | >100 | >100 | |
NSCLC | A-549/ATCC | 14.7 | 62.8 | >100 | 32.7 | 97.7 | >100 |
HOP-62 | 18.8 | 43.5 | >100 | 32.2 | >100 | >100 | |
NCI-H226 | 13.4 | 57.9 | >100 | 37.9 | 77.8 | >100 | |
NCI-H23 | 19.9 | 51.9 | >100 | 28.1 | 56.0 | 90.8 | |
NCI-H322M | 18.3 | >100 | >100 | 34.2 | 95.5 | >100 | |
NCI-H460 | 17.2 | 69.4 | >100 | 38.3 | 100 | >100 | |
NCI-H522 | 14.1 | 49.4 | >100 | 27.9 | 94.2 | >100 | |
Colon cancer | COLO 205 | 16.8 | 33.0 | 65.0 | 29.8 | 60.8 | 90.2 |
HCC-2998 | 15.5 | 31.6 | 64.3 | 31.6 | 77.6 | 98.4 | |
HCT-116 | 15.1 | 34.4 | 78.2 | 26.2 | 67.3 | 85.1 | |
HCT-15 | 6.4 | 68.3 | >100 | 35.6 | 90.2 | >100 | |
HT29 | 15.9 | 45.7 | >100 | 61.1 | >100 | >100 | |
KM12 | 13.0 | >100 | >100 | 36.1 | 98.9 | >100 | |
SW-620 | 14.4 | >100 | >100 | 35.3 | >100 | >100 | |
CNS cancer | SF-295 | 12.2 | 37.9 | >100 | 46.7 | >100 | >100 |
SF-539 | 13.1 | 29.0 | 64.4 | 28.3 | 69.2 | >100 | |
SNB-19 | 19.1 | 57.6 | >100 | 40.9 | >100 | >100 | |
U251 | 13.0 | 36.5 | >100 | 30.7 | 77.4 | >100 | |
Melanoma | M14 | 8.9 | 53.4 | >100 | 37.8 | 97.5 | >100 |
MDA-MB-435 | 18.9 | >100 | >100 | 17.6 | 48.3 | >100 | |
SK-MEL-5 | 10.9 | 36.7 | >100 | 26.8 | 74.0 | 98.2 | |
UACC-62 | 1.5 | 15.5 | >100 | 23.9 | 84.7 | >100 | |
Ovarian cancer | IGROV1 | 16.3 | 68.1 | >100 | 12.3 | 94.4 | >100 |
OVCAR-3 | 16.6 | 36.7 | 81.1 | 24.3 | 73.8 | >100 | |
OVCAR-8 | 18.6 | >100 | >100 | 40.8 | >100 | >100 | |
NCI/ADR-RES | 18.4 | >100 | >100 | – | – | – | |
Renal cancer | 786-0 | 16.1 | 43.7 | >100 | 35.3 | >100 | >100 |
A498 | 15.2 | 63.1 | >100 | 45.0 | >100 | >100 | |
ACHN | 11.6 | >100 | >100 | 29.4 | >100 | >100 | |
CAKI-1 | 6.3 | >100 | >100 | 42.8 | >100 | >100 | |
SN12C | 18.4 | >100 | >100 | 39.2 | >100 | >100 | |
UO-31 | 9.8 | 27.3 | 75.0 | 25.1 | 76.4 | >100 | |
Prostate cancer | PC-3 | 14.4 | 71.1 | >100 | 19.0 | 47.2 | >100 |
DU-145 | 17.3 | 55.7 | >100 | 24.0 | 92.0 | >100 | |
Breast cancer | MCF7 | 19.7 | 97.4 | >100 | 24.1 | 81.8 | >100 |
MDA-MB-231/ATCC | 14.6 | 63.3 | >100 | – | – | – | |
BT-549 | 16.1 | 44.7 | >100 | 32.6 | >100 | >100 | |
T-47D | 13.9 | 87.6 | >100 | 16.4 | 74.6 | >100 | |
MDA-MB-468 | 18.9 | >100 | >100 | – | – | – |
3. Experimental Section
3.1. General Procedures
3.2. Synthesis
3.2.1. Procedure for the Preparation of 4-[(5-Methyl-1,3,4-thiadiazol-2-yl)thio]-3-pyridinesulfonamide (3)
3.2.2. General Procedure for the Preparation of 4-Substituted-N-(R2-phenylcarbamoyl)-3-pyridine-sulfonamides
3.3. In Vitro Anticancer Screening
4. Conclusions
Supplementary Materials
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Szafrański, K.; Sławiński, J. Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity. Molecules 2015, 20, 12029-12044. https://doi.org/10.3390/molecules200712029
Szafrański K, Sławiński J. Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity. Molecules. 2015; 20(7):12029-12044. https://doi.org/10.3390/molecules200712029
Chicago/Turabian StyleSzafrański, Krzysztof, and Jarosław Sławiński. 2015. "Synthesis of Novel 1-(4-Substituted pyridine-3-sulfonyl)-3-phenylureas with Potential Anticancer Activity" Molecules 20, no. 7: 12029-12044. https://doi.org/10.3390/molecules200712029