Quinazoline is an

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula C₈H₆N₂. It is an

aromatic In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated system, conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugati ...

heterocycle A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

with a bicyclic structure consisting of two fused six-membered aromatic rings, a

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

ring and a

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...

ring. It is a light yellow crystalline solid that is soluble in water. Also known as 1,3-diazanaphthalene, quinazoline received its name from being an aza derivative of

quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only sl ...

. Though the parent quinazoline molecule is rarely mentioned by itself in technical literature, substituted derivatives have been synthesized for medicinal purposes such as antimalarial and anticancer agents. Quinazoline is a planar molecule. It is isomeric with the other diazanaphthalenes of the benzodiazine subgroup: cinnoline,

quinoxaline A quinoxaline, also called a benzopyrazine, in organic chemistry, is a heterocyclic compound containing a ring complex made up of a benzene ring and a pyrazine ring. It is isomeric with other naphthyridines including quinazoline, phthalazine and c ...

, and phthalazine. Over 200 biologically active quinazoline and quinoline alkaloids are identified.

Synthesis

The synthesis of quinazoline was first reported in 1895 by August Bischler and Lang through the decarboxylation of the 2-carboxy derivative (quinazoline-2-carboxylic acid). In 1903, Siegmund Gabriel reported the synthesis of the parent quinazoline from ''o''-nitrobenzylamine, which was reduced with hydrogen iodide and red phosphorus to 2-aminobenzylamine. The reduced intermediate condenses with formic acid to yield dihydroquinazoline, which was oxidized to quinazoline.Morgan, G.T., ed. ''Abstract of Papers''. Journal of the Chemical Society. London: Gurney & Jackson, 1904. Print. Methods have been reviewed. An efficient route to the parent heterocycle proceeds via the 4-chloro derivative to the tosylhydrazide, which is removed by base.

Reactions

Hydration and addition reactions

Quinazoline protonates (and methylates) at N3. Protonation induces hydration. Many mildly acidic substrates add across the C=N3 bond, these include hydrogen cyanide, sodium bisulfite, and methyl ketones.

Hydrolysis

In warm solution, quinazoline hydrolyzes under acidic and alkaline conditions to 2-Aminobenzaldehyde, 2-aminobenzaldehyde (or the products of its self-condensation) and formic acid and ammonia/ammonium.Büchel, K. H., ed. ''Methods of Organic Chemistry (Houben-Weyl): Additional and Supplementary Volumes to the 4th Edition.'' New York: Georg Thieme Verlag Stuttgart, 2001.

Electrophilic and nucleophilic substitution

The pyrimidine ring resists electrophilic substitution, although the 4-position is more reactive than the 2-position. In comparison, the benzene ring is more susceptible to electrophilic substitution. The ring position order of reactivity is 8 > 6 > 5 > 7. 2- and 4-halo derivatives of quinazoline undergo displacement by nucleophiles, such as piperidine.

Biological and pharmacological significance

Gefitinib

In May 2003, the U.S. Food and Drug Administration (FDA) approved the quinazoline gefitinib. The drug, produced by AstraZeneca, is an inhibitor of the protein kinase of epidermal growth factor receptor (EGFR). It binds to the ATP-binding site of EGFR, thus inactivating the anti-apoptotic Ras signalling cascade, anti-apoptotic Ras signal transduction cascade preventing further growth of cancer cells.

Lapatinib

In March 2007, GlaxoSmithKline's drug lapatinib was approved by the U.S. FDA to treat advanced-stage or metastatic breast cancer in combination with Hoffmann-La Roche, Roche's capecitabine. Lapatinib eliminates the growth of breast cancer stem cells that cause tumor growth. The binding of lapatinib to the ATP-binding site in the EGFR and human epidermal growth factor receptor 2 (HER2) protein kinase domains inhibits signal mechanism activation (through reversible, competitive inhibition).

Erlotinib

In May 2013, erlotinib, a drug manufactured by Astellas, was approved by the U.S. FDA to treat NSCLC patients with tumors caused by mutations of EGFR. The binding of erlotinib to the ATP-binding sites of the EGFR receptors prevents EGFR from producing phosphotyrosine residues (due to competitive inhibition), thus rendering the receptor incapable of generating signal cascades to promote cell growth.

Afatinib

In July 2013, the U.S. FDA approved afatinib, a drug developed by Boehringer Ingelheim, as an irreversible, competitive inhibitor of HER2 and EGFR kinases. While afatinib demonstrates a similar mechanism to laptinib in which it acts as an irreversible HER2 and EGFR inhibitor, afatinib has also shown activity against tyrosine kinases that have become resistant to gefinitib and erlotinib. File:Gefitinib structure.svg, Gefitinib for treatment of non-small-cell lung carcinoma. File:Lapatinib.svg, Lapatinib for treatment of advanced-stage or metastatic breast cancer. File:Erlotinib.svg, Erlotinib, an anti-tumor agent. File:Afatinib skeletal.svg, Afatinib for treatment of cancers resistant to gefinitib and erlotinib.

References

{{Authority control Quinazolines, Aromatic bases Simple aromatic rings