Quinazoline is an
organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...
with the formula C
8H
6N
2. It is an
aromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different chemical element, elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis ...
with a bicyclic structure consisting of two fused six-membered aromatic rings, a
benzene
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...
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 other ...
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
Aza or AZA may refer to:
Places
*Aza, Azerbaijan, a village and municipality
*Azadkənd, Nakhchivan or Lower Aza, Azerbaijan
*Aza, medieval name of Haza, Province of Burgos, Spain
*Aźa, a Tibetan name for the Tuyuhun kingdom
*Aza, a Hebrew roman ...
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 sli ...
. 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
In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers.
Iso ...
with the other diazanaphthalenes of the
benzodiazine subgroup:
cinnoline
Cinnoline is an aromatic heterocyclic compound with the formula C8H6N2. It is isomeric with other naphthyridines including quinoxaline, phthalazine and quinazoline.
Properties
The free base can be obtained as an oil by treatment of the hydro ...
,
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 ...
, and
phthalazine. Over 200 biologically active quinazoline and
quinoline alkaloids
Quinoline alkaloids are naturally occurring chemical compounds from the group of alkaloids, which are chemically derived from quinoline. Some quinoline alkaloids show antiseptic, convulsive or antineoplastic effects.
Examples
Alkaloids with a q ...
are identified.
Synthesis
:
The synthesis of quinazoline was first reported in 1895 by
August Bischler
August Bischler (29 April 1865 – 26 May 1957) was a Russian Empire-born ethnic Crimea German chemist who later emigrated to Switzerland. He discovered the Bischler–Möhlau indole synthesis reaction in 1892 and, together with Bernard Napier ...
and Lang through the
decarboxylation
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is t ...
of the 2-carboxy derivative (quinazoline-2-carboxylic acid).
[Asif, M. ''Chemical Characteristics, Synthetic Methods, and Biological Potential of Quinazoline and Quinazolinone Derivatives'', International Journal of Medicinal Chemistry, Article ID 395637, 2014. ] In 1903,
Siegmund Gabriel
Siegmund Gabriel (7 November 1851 – 22 March 1924) was a German chemist.
Scientific career
Siegmund Gabriel began studying chemistry at the University of Berlin in 1871. He continued his studies at the University of Heidelberg in 1872 wi ...
reported the synthesis of the parent quinazoline from ''o''-nitrobenzylamine, which was reduced with hydrogen iodide and red phosphorus to 2-amino
benzylamine
Benzylamine is an organic chemical compound with the condensed structural formula C6H5CH2NH2 (sometimes abbreviated as PhCH2NH2 or BnNH2). It consists of a benzyl group, C6H5CH2, attached to an amine functional group, NH2. This colorless water- ...
. 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
Hydrogen cyanide, sometimes called prussic acid, is a chemical compound with the formula HCN and structure . It is a colorless, extremely poisonous, and flammable liquid that boils slightly above room temperature, at . HCN is produced on an ...
,
sodium bisulfite
Sodium bisulfite (or sodium bisulphite, sodium hydrogen sulfite) is a chemical mixture with the approximate chemical formula NaHSO3. Sodium bisulfite in fact is not a real compound, but a mixture of salts that dissolve in water to give solutions ...
, and methyl ketones.
Hydrolysis
In warm solution, quinazoline hydrolyzes under acidic and alkaline conditions to
2-aminobenzaldehyde
2-Aminobenzaldehyde is an organic compound with the formula C6H4(NH2)CHO. It is one of three isomers of aminobenzaldehyde. It is a low-melting yellow solid that is soluble in water.
Preparation and reactions
It is usually prepared by reduction ...
(or the products of its self-condensation) and
formic acid
Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid, and has the chemical formula HCOOH and structure . It is an important intermediate in chemical synthesis and occurs naturally, most notably in some ants. Es ...
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
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targ ...
. The drug, produced by
AstraZeneca
AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includin ...
, is an inhibitor of the
protein kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
of
epidermal growth factor receptor
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
(EGFR). It binds to the ATP-binding site of EGFR, thus inactivating the
anti-apoptotic Ras signal transduction cascade preventing further growth of cancer cells.
Lapatinib
In March 2007,
GlaxoSmithKline
GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
's drug
lapatinib
Lapatinib ( INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts ...
was approved by the U.S. FDA to treat advanced-stage or metastatic breast cancer in combination with
Roche
F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...
's
capecitabine
Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth.
Comm ...
. 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
Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...
(HER2) protein kinase domains inhibits signal mechanism activation (through reversible, competitive inhibition).
Erlotinib
In May 2013,
erlotinib
Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) � ...
, a drug manufactured by
Astellas
is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . On February 5, 2020, the company announced management changes effective from April 1, 2020.
Astellas is a member of the Mitsubishi UFJ Fina ...
, 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
Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.
It is mainly used to treat ...
, 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
Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in targ ...
for treatment of non-small-cell lung carcinoma
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
.
File:Lapatinib.svg, Lapatinib
Lapatinib ( INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts ...
for treatment of advanced-stage or metastatic breast cancer.
File:Erlotinib.svg, Erlotinib
Erlotinib, sold under the brand name Tarceva among others, is a medication used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Specifically it is used for NSCLC with mutations in the epidermal growth factor receptor (EGFR) � ...
, an anti-tumor agent.
File:Afatinib skeletal.svg, Afatinib
Afatinib, sold under the brand name Gilotrif among others, is a medication used to treat non-small cell lung carcinoma (NSCLC). It belongs to the tyrosine kinase inhibitor family of medications. It is taken by mouth.
It is mainly used to treat ...
for treatment of cancers resistant to gefinitib and erlotinib.
See also
*
Quinazolinone
Quinazolinone is a heterocyclic chemical compound, a quinazoline with a carbonyl group in the C4N2 ring. Two isomers are possible: 2-quinazolinone and 4-quinazolinone, with the 4-isomer being the more common. These compounds are of interest in med ...
*
Niementowski quinazoline synthesis
The Niementowski quinazoline synthesis is the chemical reaction of anthranilic acids with amides to form 4-oxo-3,4-dihydroquinazolines (3''H''-quinazolin-4-ones).
Uses
Research has demonstrated that the Niementowski quinazoline synthesis could ...
References
{{reflist
Aromatic bases
Simple aromatic rings