Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines

Rick Morrison; Jasim M A Al-Rawi; Ian G Jennings; Philip E Thompson; Michael J Angove

doi:10.1016/j.ejmech.2016.01.042

Synthesis, structure elucidation, DNA-PK and PI3K and anti-cancer activity of 8- and 6-aryl-substituted-1-3-benzoxazines

Eur J Med Chem. 2016 Mar 3:110:326-39. doi: 10.1016/j.ejmech.2016.01.042. Epub 2016 Jan 27.

Authors

Rick Morrison¹, Jasim M A Al-Rawi², Ian G Jennings³, Philip E Thompson⁴, Michael J Angove⁵

Affiliations

¹ Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: rmmorrison@students.latrobe.edu.au.
² Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: j.al-rawi@latrobe.edu.au.
³ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: Ian.Jennings@monash.edu.
⁴ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: Philip.Thompson@monash.edu.
⁵ Pharmacy and Applied Science, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: m.angove@latrobe.edu.au.

PMID: 26854431
DOI: 10.1016/j.ejmech.2016.01.042

Abstract

The synthesis of 6-aryl, 8- aryl, and 8-aryl-6-chloro-2-morpholino-1,3-benzoxazines with potent activity against PI3K and DNA-PK is described. Synthesis of thirty one analogues was facilitated by an improved synthesis of 3-bromo-2-hydroxybenzoic acid 13 by de-sulphonation of 3-bromo-2-hydroxy-5-sulfobenzoic acid 12 en route to 2-methylthio-substituted-benzoxazine intermediates 17-19. From this series, compound 20k (LTURM34) (dibenzo[b,d]thiophen-4-yl) (IC50 = 0.034 μM) was identified as a specific DNA-PK inhibitor, 170 fold more selective for DNA-PK activity compared to PI3K activity. Other compounds of the series show markedly altered selectivity for various PI3K isoforms including compound 20i (8-(naphthalen-1-yl) a potent and quite selective PI3Kδ inhibitor (IC50 = 0.64 μM). Finally, nine compounds were evaluated and showed antiproliferative activity against an NCI panel of cancer cell lines. Compound 20i (8-(naphthalen-1-yl) showed strong anti-proliferative activity against A498 renal cancer cells that warrants further investigation.

Keywords: Anti-cancer activity; DNA-PK; PI3K; Suzuki coupling synthesis of 8- and 6-aryl-2-morpholino-1,3-benzoxazines.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Benzoxazines / chemical synthesis
Benzoxazines / chemistry*
Benzoxazines / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
DNA-Activated Protein Kinase / antagonists & inhibitors*
DNA-Activated Protein Kinase / metabolism
Humans
Naphthalenes / chemical synthesis
Naphthalenes / chemistry
Naphthalenes / pharmacology
Neoplasms / drug therapy
Neoplasms / enzymology
Neoplasms / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Structure-Activity Relationship
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / pharmacology

Substances

Antineoplastic Agents
Benzoxazines
Naphthalenes
Phosphoinositide-3 Kinase Inhibitors
Thiophenes
DNA-Activated Protein Kinase