Synonym
COTI-2; COTI2; COTI 2
IUPAC/Chemical Name
(E)-N'-(6,7-dihydroquinolin-8(5H)-ylidene)-4-(pyridin-2-yl)piperazine-1-carbothiohydrazide
InChi Key
UTDAKQMBNSHJJB-CJLVFECKSA-N
InChi Code
InChI=1S/C19H22N6S/c26-19(23-22-16-7-3-5-15-6-4-10-21-18(15)16)25-13-11-24(12-14-25)17-8-1-2-9-20-17/h1-2,4,6,8-10H,3,5,7,11-14H2,(H,23,26)/b22-16+
SMILES Code
S=C(N1CCN(C2=NC=CC=C2)CC1)N/N=C3CCCC4=C\3N=CC=C4
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
COTI-2 is a third generation activator of p53 mutant forms and inhibitor of the PI3K/AKT/mTOR pathway.
In vitro activity:
COTI-2 demonstrated effective anti-proliferative activity against solid epithelial cancer and leukemia cell lines (Figure 1B). Despite sharing common mutations, human cancers are strikingly heterogeneous, even among similar types of cancers, thus making them difficult to treat. This study therefore assessed the efficacy of COTI-2 against multiple human cancer cell lines representing common human malignancies, allowing assessment of effectiveness of COTI-2 in cell lines with various mutations including; TP53 (HT-29, HCT-15, OVCAR-3, K562, SF-268, SNB-19, T47D, MDA-MB-231), KRAS (MDA-MB-231, SW620), PIK3CA (MCF7, HT-29, T47D), APC (COLO-205, HCT-15), and PTEN (SF-295, SNB-19). COTI-2 appears to be a cytotoxic agent since it inhibited cellular proliferation by inducing apoptosis in cancer cells (Figure 4). COTI-2-mediated cellular death was prevented when cancer cells were pre-treated with the pan-caspase inhibitor Z-VAD-FMK, confirming the activation of caspase cascades upon treatment with COTI-2 (Figure 4B).
Reference: Oncotarget. 2016 Jul 5; 7(27): 41363–41379. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173065/
In vivo activity:
This study assessed the effectiveness of COTI-2 in inhibiting the growth of Jurkat xenografts in immunocompromised mice when administered intraperitoneally (IP). COTI-2 significantly inhibited tumor growth in the Jurkat xenografts at a dose of 10 mg/kg (Figure 5(a)). This study further determined apoptosis in tumor tissue of leukemia xenograft using TdT-mediated dUTP-biotin nick-end labeling (TUNEL) assay. TUNEL-positive apoptotic cells of tumor sections significantly increased in COTI-2-treated Jurkat xenograft mice compared with the control groups (Figure 5(b)). Exposure of mice to COTI-2 also caused a rapid increase in immunoreactivity for cleaved-caspase-3 in tumor sections (Figure 5(c)), indicative of apoptosis. Furthermore, miR-203 expression in tumor sections of Jurkat xenograft mice increased upon COTI-2 treatment (Figure 5(d)). Such findings suggest that COTI-2-mediated antileukemic activity in vivo is associated with the upregulation of miR-203.
Reference: Bioengineered. 2020; 11(1): 201–208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039633/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
3.0 |
8.19 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
366.48
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Maleki Vareki S, Salim KY, Danter WR, Koropatnick J. Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines. PLoS One. 2018 Jan 24;13(1):e0191766. doi: 10.1371/journal.pone.0191766. PMID: 29364966; PMCID: PMC5783418.
2. Salim KY, Maleki Vareki S, Danter WR, Koropatnick J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget. 2016 Jul 5;7(27):41363-41379. doi: 10.18632/oncotarget.9133. Erratum in: Oncotarget. 2017 Sep 1;8(36):60724. PMID: 27150056; PMCID: PMC5173065.
3. Guo Y, Zhu X, Sun X. COTI-2 induces cell apoptosis in pediatric acute lymphoblastic leukemia via upregulation of miR-203. Bioengineered. 2020 Dec;11(1):201-208. doi: 10.1080/21655979.2020.1729927. PMID: 32063077; PMCID: PMC7039633.
4. Lindemann A, Patel AA, Silver NL, Tang L, Liu Z, Wang L, Tanaka N, Rao X, Takahashi H, Maduka NK, Zhao M, Chen TC, Liu W, Gao M, Wang J, Frank SJ, Hittelman WN, Mills GB, Myers JN, Osman AA. COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms. Clin Cancer Res. 2019 Sep 15;25(18):5650-5662. doi: 10.1158/1078-0432.CCR-19-0096. Epub 2019 Jul 15. PMID: 31308060; PMCID: PMC6759991.
In vitro protocol:
1. Maleki Vareki S, Salim KY, Danter WR, Koropatnick J. Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines. PLoS One. 2018 Jan 24;13(1):e0191766. doi: 10.1371/journal.pone.0191766. PMID: 29364966; PMCID: PMC5783418.
2. Salim KY, Maleki Vareki S, Danter WR, Koropatnick J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget. 2016 Jul 5;7(27):41363-41379. doi: 10.18632/oncotarget.9133. Erratum in: Oncotarget. 2017 Sep 1;8(36):60724. PMID: 27150056; PMCID: PMC5173065.
In vivo protocol:
1. Guo Y, Zhu X, Sun X. COTI-2 induces cell apoptosis in pediatric acute lymphoblastic leukemia via upregulation of miR-203. Bioengineered. 2020 Dec;11(1):201-208. doi: 10.1080/21655979.2020.1729927. PMID: 32063077; PMCID: PMC7039633.
2. Lindemann A, Patel AA, Silver NL, Tang L, Liu Z, Wang L, Tanaka N, Rao X, Takahashi H, Maduka NK, Zhao M, Chen TC, Liu W, Gao M, Wang J, Frank SJ, Hittelman WN, Mills GB, Myers JN, Osman AA. COTI-2, A Novel Thiosemicarbazone Derivative, Exhibits Antitumor Activity in HNSCC through p53-dependent and -independent Mechanisms. Clin Cancer Res. 2019 Sep 15;25(18):5650-5662. doi: 10.1158/1078-0432.CCR-19-0096. Epub 2019 Jul 15. PMID: 31308060; PMCID: PMC6759991.
1: Maleki Vareki S, Salim KY, Danter WR, Koropatnick J. Novel anti-cancer drug COTI-2 synergizes with therapeutic agents and does not induce resistance or exhibit cross-resistance in human cancer cell lines. PLoS One. 2018 Jan 24;13(1):e0191766. doi: 10.1371/journal.pone.0191766. eCollection 2018. PubMed PMID: 29364966.
2: Heffeter P, Pape VFS, Enyedy EA, Keppler BK, Szakas G, Kowol CR. Anticancer thiosemicarbazones: chemical properties, interaction with iron metabolism, and resistance development. Antioxid Redox Signal. 2018 Jan 15. doi: 10.1089/ars.2017.7487. [Epub ahead of print] PubMed PMID: 29334758.
3: Salim KY, Vareki SM, Danter WR, San-Marina S, Koropatnick J. Correction: COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget. 2017 Sep 1;8(36):60724. doi: 10.18632/oncotarget.20600. eCollection 2017 Sep 1. PubMed PMID: 29062467; PubMed Central PMCID: PMC5601175.
4: Duffy MJ, Synnott NC, Crown J. Mutant p53 as a target for cancer treatment. Eur J Cancer. 2017 Sep;83:258-265. doi: 10.1016/j.ejca.2017.06.023. Epub 2017 Jul 28. Review. PubMed PMID: 28756138.
5: Salim KY, Maleki Vareki S, Danter WR, Koropatnick J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget. 2016 Jul 5;7(27):41363-41379. doi: 10.18632/oncotarget.9133. Erratum in: Oncotarget. 2017 Sep 1;8(36):60724. PubMed PMID: 27150056; PubMed Central PMCID: PMC5173065.
