US 11,578,040 B2Granted

[5]Helicene derivatives as molecular reporters for diagnostic applications and methods of synthesis therefor

AssigneeNational Science and Technology Development Agency

InventorsThanasat Sooksimuang, Nitsara Karoonuthaisiri, Ratthaphol Charlermroj, Somboon Sahasithiwat, Waraporn Panchan, Manlika Makornwattana, Sudtida Phuengwas, Laongdao Kangkaew

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Abstract

The present invention provides the methods of synthesis of [5]helicene compounds and the use of the said compounds conjugating with biomolecules to work as molecular reporter for diagnostic. The compounds in the present invention have the chemical structure illustrated in the formula (1): wherein G is a connecting group composes of 2 carbon atoms selected from the group consisting of ethane and ethylene; A is a separated or connected group selected from the group consisting of cyano and imide; D1 is selected from the group consisting of oxyalkanoic acid, oxyalkanal and oxyalkanesulfonate; and D2 has structure selected from the group consisting of hydroxyl, oxyalkanoic acid, oxyalkanal, alkyl oxyalkanoate, oxyalkanol and oxyalkanesulfonate. The compounds in the present invention compose of aromatic [5]helicene core comprising long it-conjugating system. The said compounds contain functional groups which able to link with biomolecules and they are soluble in water or other solvents that used in binding process with biomolecules. Moreover, owing to having proper chemical structure, the compounds in the present invention exhibit good fluorescent emission in wavelength of 425-675 nm. When the said compounds connected with biomolecules, the biomolecules give good fluorescence and can be detected under ultraviolet radiation.

Claims10

Dependent claims

A helicene derivative compound represented by the following chemical formula (1)

wherein:
G is a connecting group comprising 2 carbon atoms selected from the group consisting of
Ethane
and
Ethylene
A is a separated or connected group selected from the group consisting of
Cyano
—CN and
Imide
wherein R1 is selected from the group consisting of
Phenyl
Alkyl
when a is a number of carbon atoms in aliphatic hydrocarbon and a ranges from 1 to 7;
and
Alkanoic acid
when b is a number of carbon atoms in aliphatic hydrocarbon and b ranges from 1 to 7;
D1 is selected from the group consisting of
Oxyalkanoic acid
when n is a number of carbon atoms in aliphatic hydrocarbon and n ranges from 1 to 7;
Oxyalkanal
when n is a number of carbon atoms in aliphatic hydrocarbon and n ranges from 1 to 7;
and
Oxyalkanesulfonate
when M is a metal atom selected from the group consisting of sodium and potassium,
m is a number of carbon atoms in aliphatic hydrocarbon and m ranges from 3 or 4;
D2 is selected from the group consisting of
Hydroxy
—OH
Oxyalkanoic acid
when y is a number of carbon atoms in aliphatic hydrocarbon and y ranges from 1 to 7;
Oxyalkanal
when y is a number of carbon atoms in aliphatic hydrocarbon and y ranges from 1 to 7;
Alkyl oxyalkanoate
when y is a number of carbon atoms in aliphatic hydrocarbon and y ranges from 1 to 7,
R2 is selected from the group consisting of methyl and ethyl group;
Oxyalkanol
when z is a number of carbon atoms in aliphatic hydrocarbon and z ranges from 2 to 8;
and
Oxyalkanesulfonate
when M is a metal atom selected from the group consisting of sodium and potassium,
m is a number of carbon atoms in aliphatic hydrocarbon and m ranges from 3 or 4.

38 more elements

A method of preparing a [5]helicene derivative compound, comprising the steps of:

a) an O-alkylation reaction of the [5]helicene compound in formula (4), selected from the [5]helicene compound in formula (4) wherein A1 is an imide or a cyano, with an haloalkanoic acid alkyl ester (I) with a first base in a first organic solvent to give [5]helicene compound (5) and/or compound (6) as an intermediate molecule;
wherein the haloalkanoic acid alkyl ester (I) has a chemical formula:
wherein n is a number of carbon atoms of aliphatic hydrocarbon in the haloalkanoic acid alkyl ester (I) where n ranges from 1 to 7;
wherein the first base is selected from the group consisting of sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3), sodium carbonate (Na2CO3), and potassium carbonate (K2CO3), wherein the first organic solvent is selected from the group consisting of dimethyl formamide, acetone, acetonitrile, and a mixture thereof;
b) a hydrolysis reaction of the [5]helicene compound (5) or compound (6) with a second base in a second organic solvent at a temperature in the range of 25-150° C. for 1-24 hours, followed by an acid treatment with an acid at a pH of 0 to obtain [5]helicene compound (7) or compound (8) as a final product or an intermediate;
wherein the second base is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), and lithium hydroxide (LiOH), wherein the organic solvent 2 is selected from the group consisting of ethanol, methanol, tetrahydrofuran, dioxane, dichloromethane, and a mixture thereof, and wherein the acid is selected from the group consisting of hydrochloric acid, and sulfuric acid;
c) an O-alkylation reaction of the intermediate compound containing an OH group, selected from [5]helicene compounds (4), (5) or (7), with an alkane sultone (II) and a third base in a third organic solvent to obtain [5]helicene compound (9), compound (10) or compound (11) as final product of intermediate;
wherein the alkane sultone (II) is a straight chain and has a chemical formula:
wherein m is a number of carbon atoms in aliphatic hydrocarbon and equals 3 or 4;
wherein the third base is selected from the group consisting of sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium methoxide (NaOMe), potassium methoxide (KOMe), sodium ethoxide (NaOEt), and potassium ethoxide (KaOEt), wherein the third organic solvent is selected from the group consisting of methanol, ethanol, acetone, and acetonitrile;
and
d) a reduction reaction of the intermediate containing ester group, selected from [5]helicene compounds (5), (6), or (10), using diisobutylaluminum hydride, (DIBAL-H) in a fourth organic solvent to obtain a [5]helicene compound (12), compound (13) and/or compound (14) and/or compound (15), or compound (16) as a final product
wherein the fourth organic solvent is selected from the group consisting of dichloromethane, tetrahydrofuran, toluene, and a mixture thereof.

10 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/338,031Filed 29 Sep 2017
Priority: TH 160100588730 Sep 2016
Published: US 2020/0017443 A116 Jan 2020
Granted: 14 Feb 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 209/58
Ring systems containing three or more rings: [b]- or [c]-condensed
C07C 255/54
Having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton: containing cyano groups and etherified hydroxy…
C07C 309/11
Containing etherified hydroxy groups bound to the carbon skeleton: with the oxygen atom of at least one of the etherified hydroxy groups further…
G01N 33/582
Involving labelled substances: with fluorescent label