3-(2,4-dichlorophenyl)-3-oxo-2-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-ylidene)propanenitrile

• ChemBase ID: 154756
• Molecular Formular: C17H9Cl2N3O2
• Molecular Mass: 358.17826
• Monoisotopic Mass: 357.0071819
• SMILES: c1ccc2c(c1)c(=O)[nH]/c(=C(\C#N)/C(=O)c1ccc(cc1Cl)Cl)/[nH]2
• Canonical SMILES: N#C/C(=c/1\[nH]c(=O)c2c([nH]1)cccc2)/C(=O)c1ccc(cc1Cl)Cl
• InChI: InChI=1S/C17H9Cl2N3O2/c18-9-5-6-10(13(19)7-9)15(23)12(8-20)16-21-14-4-2-1-3-11(14)17(24)22-16/h1-7,21H,(H,22,24)
• InChIKey: SESYPWCSIZUIAS-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 3-(2,4-dichlorophenyl)-3-oxo-2-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-ylidene)propanenitrile
• IUPAC Traditional name: 3-(2,4-dichlorophenyl)-3-oxo-2-(4-oxo-1,3-dihydroquinazolin-2-ylidene)propanenitrile
• Synonyms: 2,4-Dichloro-a-(3,4-dihydro-4-oxo-2(1H)-quinazolinylidene)-β-oxo-benzenepropanenitrile; Ciliobrevin A; Hedgehog Pathway Inhibitor 4; HPI-4

Database IDs

• CAS Number: 302803-72-1
• MDL Number: MFCD01911757
• PubChem SID: 162248894
• PubChem CID: 6883982

CALCULATED PROPERTIES

• Acid pKa: 11.232669
• H Acceptors: 4
• H Donor: 2
• LogD (pH = 5.5): 4.141699
• LogD (pH = 7.4): 4.1416416
• Log P: 4.1417
• Molar Refractivity: 102.7322 cm^3
• Polarizability: 34.01831 Å^3
• Polar Surface Area: 81.99 Å^2
• Rotatable Bonds: 2
• Lipinski's Rule of Five: true

PROPERTIES

Physical Property

• Solubility: DMSO: >20 mg/mL
• Apperance: yellow powder

Safety Information

• European Hazard Symbols: Nature polluting (N); Harmful (Xn)
• UN Number: 3077
• German water hazard class: 3
• Hazard Class: 9
• Packing Group: 3
• Risk Statements: 22-50/53
• Safety Statements: 60-61
• GHS Pictograms: GHS07; GHS09
• GHS Signal Word: Warning
• GHS Hazard statements: H302-H410
• GHS Precautionary statements: P273-P501
• RID/ADR: UN 3077 9/PG 3
• Storage Temperature: 2-8°C

Product Information

• Purity: ≥98% (HPLC)
• Empirical Formula (Hill Notation): C17H9Cl2N3O2

DETAILS

Sigma Aldrich - H4541

Biochem/physiol Actions
HPI-4 is a Hedgehog pathway inhibitor; ciliogenesis inhibitor. The Hedgehog (HH) signaling pathway is targeted for anti-cancer therapeutics. A key signaling molecule in HH pathway, Smoothened (Smo), has been the target of pharmacological intervention, which has resulted in multiple Smo antagonists including Cyclopamine. However, the oncogenic form of Smo is resistant to Cyclopamine, so the identification of inhibitors of downstream effectors, such as the transcription factors Gli1 and Gli2, is important. Four small molecules were identified to inhibit HH downstream of Smo, HPI-1, HPI-2, HPI-3, and HPI-4. HPI-4 blocked HH pathway activation by SAG, decreased Smo ciliary accumulation, decreased HH activity in a consitutively active HH cell line, and decreased Gli1 and Gli2, processing, and stability. HPI-4 inhibited proliferation of cerebellar granula neuron precursor cells, an important model of HH signaling. Cilia in HPI-4-treated cells were either truncated or absent. The mechanism of action of HPI-4 is hypothesized to be directly through perturbation of ciliogenesis, leading to disruption of Gli1/Gli2 activity, which is distinctly different from that of Cyclopamine.