Physicochemical Properties
| Molecular Formula | C28H27CLF2N8O5S |
| Molecular Weight | 661.0794 |
| Exact Mass | 660.148 |
| Elemental Analysis | C, 50.87; H, 4.12; Cl, 5.36; F, 5.75; N, 16.95; O, 12.10; S, 4.85 |
| CAS # | 2565705-02-2 |
| PubChem CID | 145704695 |
| Appearance | White to light yellow solid powder |
| LogP | 4.5 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 15 |
| Rotatable Bond Count | 9 |
| Heavy Atom Count | 45 |
| Complexity | 1090 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | COC1=NC(=NC(=N1)N2CCNCC2)NC3=C(C=CC(=C3)S(=O)(=O)C)N[C@@H](C4=C5C(=CC=C4)OC(O5)(F)F)C6=C(C=CC=N6)Cl |
| InChi Key | QJIMSJUUARCROQ-QFIPXVFZSA-N |
| InChi Code | InChI=1S/C28H27ClF2N8O5S/c1-42-27-37-25(36-26(38-27)39-13-11-32-12-14-39)35-20-15-16(45(2,40)41)8-9-19(20)34-22(23-18(29)6-4-10-33-23)17-5-3-7-21-24(17)44-28(30,31)43-21/h3-10,15,22,32,34H,11-14H2,1-2H3,(H,35,36,37,38)/t22-/m0/s1 |
| Chemical Name | 1,2-Benzenediamine, N1-[(S)-(3-chloro-2-pyridinyl)(2,2-difluoro-1,3-benzodioxol-4-yl)methyl]-N2-[4-methoxy-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-4-(methylsulfonyl)- |
| Synonyms | Dot1L-IN4Dot1L-IN-4Dot1L-IN 4 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | Dot1L-IN-4 (Compound 10) was examined in cellular assays to assess its capacity to suppress HOXA9 gene expression in Molm-13 cells (ED50 HOXA9 RGA=33)nm) and H3K79 dimethylation in HeLa cells (ED50 H3K79me2 Elisa=1.7 nM). Additionally, dot1L-IN-4, with an IC50 of 99 µM, inhibits mixed lineage leukemia (MLL) [1]. |
| ln Vivo | At such high doses, tumor-bearing xenograft mice did not tolerate Dot1L-IN-4 (Compound 10; 300 mg/kg; po; qd); at 6-fold decreased doses, however, tumors and the HOXA9 reporter increased. The reduction in gene mRNA was less than half as compared to control animals [1]. |
| Animal Protocol |
Animal/Disease Models: Male mice (C57BL/6) with subcutaneousMV4-11 tumor xenografts [1] Doses: 300 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: Po Experimental Results: With tumor xenografts The mice were unable to tolerate such high doses, and tumor growth as well as HOXA9 reporter mRNA was diminished by less than half when the dose was diminished 6-fold compared with control animals. |
| References |
[1]. New Potent DOT1L Inhibitors for in Vivo Evaluation in Mouse. ACS Med. Chem. Lett. 2019, 10, 12, 1655-1660. |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 220 mg/mL (~332.79 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (3.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (3.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5127 mL | 7.5634 mL | 15.1268 mL | |
| 5 mM | 0.3025 mL | 1.5127 mL | 3.0254 mL | |
| 10 mM | 0.1513 mL | 0.7563 mL | 1.5127 mL |