CN105726544A - Antitumor application of small-molecule organic compound - Google Patents
Antitumor application of small-molecule organic compound Download PDFInfo
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- CN105726544A CN105726544A CN201610197227.9A CN201610197227A CN105726544A CN 105726544 A CN105726544 A CN 105726544A CN 201610197227 A CN201610197227 A CN 201610197227A CN 105726544 A CN105726544 A CN 105726544A
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- compound
- small
- ido1
- organic compound
- molecule organic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
Abstract
The invention relates to the field of medical chemistry, and in particular relates to an application of an organic small-molecule compound (I), which is discovered through virtual screening on the basis of bioinformatics and a computer aided design technology and is represented by FN-01, in preparation of an antitumor drug, and also relates to a pharmaceutical composition containing the type of compound.
Description
Technical field
The invention belongs to medicinal chemistry arts, be specifically related to a kind of based on bioinformatics and computer-aided design skill
Art, finds the application in preparing antitumor drug of the class organic micromolecule compound with FN-01 as representative through virtual screening,
And comprise the pharmaceutical composition of this compounds.
Background technology
Indole amine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) is a kind of containing ferrous blood red
The oxidoreductase of element, belongs to monomeric enzyme, is made up of 403 amino acid residues.Divide two hypotypes, i.e. IDO1 and IDO2.IDO is liver
Uniquely can be catalyzed the enzyme of tryptophan metabolism beyond dirty, catalysis tryptophan follows kynurenine pathway metabolism in vivo, and this approach is born
Tryptophan more than 95% in duty metabolism human body.IDO is the rate-limiting enzyme of kynurenine pathway.
Early clinic finds, there is the phenomenon that tryptophan metabolism level improves, studied table later in many tumor tissues
It is bright that it is relevant with IDO expression raising.When IDO is in the tissue in overexpression, kynurenine pathway can be made to express in " high
Put forth energy " state, thus cause tryptophan metabolism to exhaust.T lymphocyte tryptophan is especially sensitive, and the decline of tryptophan levels makes it
Generating function obstacle, growth retardation is in the G1 phase, thus loses the immunne response to tumor cell.Based on this mechanism, IDO can
Make fetus exempt from the attack of mother's immune system, but result also in the immunologic escape of tumor simultaneously.Except the immunity with tumor is escaped
Escaping relevant, IDO is proved also relevant to some nervous system disease, as there are some researches show IDO and kynurenine pathway at A Er
The pathogenesis of Zi Haimo sick (AD) plays key player (Stone, T, W., et al., J.Alzheimers
Dis.2001,3:355-66；Guillemin,G.J.et al,.Redox Rep 2002,7,199-20).Thus, IDO conduct
A kind of emerging drug targets rapidly becomes the study hotspot of medicinal chemistry art.
That research at present is relatively more is IDO1, and existing a large amount of scientific research institutions and drugmaker put into IDO1 suppression in recent years
In the middle of the research of agent, and achieve very fast progress.Have three molecules at present and enter clinical research, i.e. D type methyl tryptophan (D-
1MT), code name be INCB024360 (epacadostat) and NLG919, there is presently no go through listing IDO1 suppression
Agent.In general, the structure type of IDO1 inhibitor is the most less, and most inhibitor there is also, and suppression efficiency is the highest, effect machine
Make the defects such as the most indefinite.Therefore, find the IDO1 inhibitor of brand new, to exploitation IDO1 inhibitor series antineoplastic medicament still
It is significant.
Summary of the invention
Inventor uses molecular docking software Discovery Studio 3.0 to the CHEMDIV data sub very much containing 130
Storehouse is searched, and is respectively adopted Pharmacophore Model, class medicine five rule and molecular docking (CDOEKER) and carries out step-sizing, it is desirable to
Find the lead compound with the IDO1 inhibitor of brand new, lay the foundation for exploitation antineoplastic immune medicine.
This research has architectural feature and the basis of crystal complex binding pattern of IDO1 inhibitor in fully investigation
On, it is aided with rational screening technique, carries out the research work of large-scale virtual screening new construction type IDO1 inhibitor.?
The rear IDO1 inhibitor being successfully found that some known structure types, such as indole derivatives, 4-phenylimidazole analog derivative etc.,
This is the reliability of screening technique from side illustration.
The present invention relates to the class organic micromolecule compound with FN-01 as representative for preparing in antitumor drug
Application, concrete formula is as follows:
Wherein n=1-4
The compound that formula above is comprised is commercially available or can be used existing by those of ordinary skill in the art
Synthetic route is prepared without creative work, and the anticancer usage that these compounds are had also has no that document is reported.This formula
Contained lactams and benzo hexa-member heterocycle structure, be this compounds key with IDO1 inhibitor activity, and R replaces hydro carbons
Side chain can produce hydrophobic interaction with avtive spot A pocket, is the key of such structure-activity lifting.
It is furthermore preferred that n=2, R=CH3Time, compound (I) is purchased from CHEMDIV company, is called for short FN-01, and its structure is as follows:
Above-mentioned molecule is carried out anti tumor activity in vitro test, found that the inhibitory activity of IDO1 is by compound (I)
IC50=540nM, illustrates that compound has potential anti-tumor activity.This compound compares the most already present IDO1 inhibitor, bone
Frame is novel, and has certain inhibitory activity to IDO1, shows have good DEVELOPMENT PROSPECT.
Detailed description of the invention
Embodiment 1
The anti-tumor activity experiment of compound (I) (FN-01)
The compound FN-01 of the present invention is carried out IDO1 Inhibition test, the pharmacology examination of the compounds of this invention has been presented herein below
Test and result:
The pyrrole ring oxicracking that IDO enzyme can be catalyzed on tryptophan produces N '-formylkynurenine.In room temperature
Under environment, by the L-Trp mixing of the IDO enzyme of 40nM and 900uM, and add reaction buffer (20mM ascorbate,
3.5uM methylene blue and 0.2mg/mL catalase in 50mM potassium phosphate buffer
PH 6.5), room temperature reaction three hours, in microplate reader, then carry out ultraviolet determination, detection wavelength is that 321nm. instrument is read
Number is scaled: %activity=[(A-Ab)/(At-Ab)] × 100, then with Prism GraphPad sofeware software
The Fitting Calculation IC50Value.
Result of the test is shown in Table 1:
Table 1.FN-01 is to IDO1 inhibition test
| Sample number | Title | IC50(nM) |
| 1 | FN-01 | 540 |
| 2 | INCB024360 | 118 |
Claims (1)
1. the compound of having structure formula (I) or its pharmaceutically acceptable salt are for preparing the purposes of antitumor drug:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610197227.9A CN105726544B (en) | 2016-03-31 | 2016-03-31 | A kind of anticancer usage of small molecular organic compounds FN-01 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610197227.9A CN105726544B (en) | 2016-03-31 | 2016-03-31 | A kind of anticancer usage of small molecular organic compounds FN-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105726544A true CN105726544A (en) | 2016-07-06 |
| CN105726544B CN105726544B (en) | 2018-06-26 |
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| CN201610197227.9A Active CN105726544B (en) | 2016-03-31 | 2016-03-31 | A kind of anticancer usage of small molecular organic compounds FN-01 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098877A (en) * | 2004-07-13 | 2008-01-02 | 不列颠哥伦比亚大学 | Indoleamine 2,3-dioxygenase (ido) inhibitors |
-
2016
- 2016-03-31 CN CN201610197227.9A patent/CN105726544B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101098877A (en) * | 2004-07-13 | 2008-01-02 | 不列颠哥伦比亚大学 | Indoleamine 2,3-dioxygenase (ido) inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| MOHAMMAD NEAZ MORSHED ET AL.: "Computational approach to the identification of novel Aurora-A inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 张防正等: "吲哚胺2，3双加氧酶的免疫调节功能研究新进展", 《中国免疫学杂志》 * |
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| CN105726544B (en) | 2018-06-26 |
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