CN105726544B - A kind of anticancer usage of small molecular organic compounds FN-01 - Google Patents
A kind of anticancer usage of small molecular organic compounds FN-01 Download PDFInfo
- Publication number
- CN105726544B CN105726544B CN201610197227.9A CN201610197227A CN105726544B CN 105726544 B CN105726544 B CN 105726544B CN 201610197227 A CN201610197227 A CN 201610197227A CN 105726544 B CN105726544 B CN 105726544B
- Authority
- CN
- China
- Prior art keywords
- compound
- ido1
- organic compounds
- small molecular
- molecular organic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medicinal chemistry arts, bioinformatics and Computer-aided Design Technology are based on more particularly to one kind, it finds a kind of for organic micromolecule compound (I) application in preparation of anti-tumor drugs of representative and to include the pharmaceutical composition of this kind of compound with FN 01 through virtual screening.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to one kind is based on bioinformatics and CAD skill
Art finds one kind using FN-01 as the organic micromolecule compound application in preparation of anti-tumor drugs of representative through virtual screening,
And include the pharmaceutical composition of this kind of compound.
Background technology
Indole amine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) is a kind of containing ferrous blood red
The oxidoreducing enzyme of element belongs to monomeric enzyme, is made of 403 amino acid residues.It is divided to two hypotypes, i.e. IDO1 and IDO2.IDO is liver
The enzyme of tryptophan metabolism can be uniquely catalyzed other than dirty, tryptophan is catalyzed in vivo and follows kynurenine pathway metabolism, and the approach is born
It is more than 95% tryptophan in duty metabolism human body.IDO is the rate-limiting enzyme of kynurenine pathway.
Early clinic is found, there are the phenomenon that the raising of tryptophan metabolism level in many tumor tissues, studies table later
It is bright that it is related with IDO expression raisings.When IDO is in the tissue overexpression, kynurenine pathway expression can be made in " high
Put forth energy " state, it is exhausted so as to cause tryptophan metabolism.T lymphocyte tryptophans are especially sensitive, and the decline of tryptophan levels makes it
Dysfunction occurs, growth retardation is in the G1 phases, so as to lose the immune response to tumour cell.Based on this mechanism, IDO can
Make fetus from the attack of mother's immune system, but also result in the immunologic escape of tumour simultaneously.In addition to escaping with the immune of tumour
It escapes related, IDO is proved also related to some the nervous system diseases, and such as some researches show that IDO and kynurenine pathways in A Er
Key player (Stone, T, W., et al., J.Alzheimers are played in the pathogenesis of Zi Haimo diseases (AD)
Dis.2001,3:355-66；Guillemin,G.J.et al,.Redox Rep 2002,7,199-20).Thus, IDO conducts
A kind of emerging drug targets rapidly become the research hotspot of medicinal chemistry art.
That research is more at present is IDO1, has a large amount of scientific research institutions in recent years and drugmaker puts into IDO1 inhibition
In the research of agent, and achieve very fast progress.Enter clinical research, i.e. D types methyl tryptophan (D- there are three molecule at present
1MT), code name is INCB024360 (epacadostat) and NLG919, and there is presently no the IDO1 inhibition for the listing that goes through
Agent.In general, the structure type of IDO1 inhibitor is also less, and the also presence of most inhibitor inhibits inefficient, effect machine
The defects of system is also indefinite.Therefore, the IDO1 inhibitor of brand new is found, to exploitation IDO1 inhibitors antitumor drugs object still
It is of great significance.
Invention content
Inventor is using molecular docking software Discovery Studio 3.0 to containing 130 CHEMDIV data sub very much
Library is respectively adopted Pharmacophore Model, five rule of class medicine and molecular docking (CDOEKER) and carries out step-sizing, it is expected into line search
It was found that the lead compound of the IDO1 inhibitor with brand new, lays the foundation for exploitation antineoplastic immune drug.
This research has the structure feature of IDO1 inhibitor and the basis of crystal complex binding pattern in abundant investigation
On, it is aided with rational screening technique, has carried out the research work of large-scale virtual screening new construction type IDO1 inhibitor.Most
It is successfully found that the IDO1 inhibitor of some known structure types, such as indole derivatives, 4- phenylimidazole analog derivatives afterwards,
This is from the reliability of side illustration screening technique.
Using FN-01 it is the organic micromolecule compound of representative in antitumor drug is used to prepare the present invention relates to one kind
Using specific general formula is as follows：
Wherein n=1-4
The compound that formula above is included is commercially available or can be by those of ordinary skill in the art using existing
Synthetic route is prepared without creative work, and anticancer usage possessed by these compounds also has no document report.The general formula
Contained lactams and benzo hexa-member heterocycle structure are the key that such compound has IDO1 inhibitor activities, R substitution hydro carbons
Branch can generate hydrophobic effect with active site A pockets, be the key that such structure-activity is promoted.
It is furthermore preferred that n=2, R=CH3When, compound (I) is purchased from CHEMDIV companies, abbreviation FN-01, and structure is as follows：
Anti tumor activity in vitro test is carried out to above-mentioned molecule, as a result, it has been found that compound (I) is to the inhibitory activity of IDO1
IC50=540nM illustrates that compound has potential antitumor activity.The compound is compared to existing IDO1 inhibitor, bone
Frame is novel, and has certain inhibitory activity to IDO1, shows there is good development prospect.
Specific embodiment
Embodiment 1
The antitumor activity experiment of compound (I) (FN-01)
IDO1 Inhibition tests are carried out to the compound of the present invention FN-01, here is the pharmacology examination of the compounds of this invention
It tests and result：
The pyrrole ring oxicracking that IDO enzymes can be catalyzed on tryptophan generates N '-formylkynurenine.In room temperature
Under environment, by the L-Trp of the IDO enzymes of 40nM and 900uM mix, and add in reaction buffer (20mM ascorbate,
3.5uM methylene blue and 0.2mg/mL catalase in 50mM potassium phosphate buffer
PH 6.5), three hours are being reacted at room temperature, ultraviolet determination is then carried out in microplate reader, Detection wavelength is read for 321nm. instruments
Number is scaled：%activity=[(A-Ab)/(At-Ab)] × 100, then with Prism GraphPad sofeware softwares
The Fitting Calculation IC50Value.
Result of the test is shown in Table 1：
Table 1.FN-01 inhibits to test to IDO1
| Sample number | Title | IC50(nM) |
| 1 | FN-01 | 540 |
| 2 | INCB024360 | 118 |
Claims (1)
- Press down 1. the compound of having structure formula (I) or its pharmaceutically acceptable salt are used to prepare indoles amine -2,3- dioxygenases 1 The purposes of preparation：
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 CN105726544A (en) | 2016-07-06 |
| CN105726544B true CN105726544B (en) | 2018-06-26 |
Family
ID=56253208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610197227.9A Active CN105726544B (en) | 2016-03-31 | 2016-03-31 | A kind of anticancer usage of small molecular organic compounds FN-01 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105726544B (en) |
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 |
|---|
| Computational approach to the identification of novel Aurora-A inhibitors;Mohammad Neaz Morshed et al.;《Bioorganic & Medicinal Chemistry》;20101204;第19卷;第907-916页，补充数据1化合物25,31 * |
| 吲哚胺2，3双加氧酶的免疫调节功能研究新进展;张防正等;《中国免疫学杂志》;20111231;第27卷(第1期);第93-95页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105726544A (en) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Qin et al. | Selective histone deacetylase small molecule inhibitors: recent progress and perspectives | |
| Espíndola et al. | Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma Cruzi Cruzain | |
| Weng et al. | Recent discovery of indoleamine-2, 3-dioxygenase 1 inhibitors targeting cancer immunotherapy | |
| WO2018068666A1 (en) | Microtubule protein inhibitor | |
| Wu et al. | Optimization of 2-(3-(arylalkyl amino carbonyl) phenyl)-3-(2-methoxyphenyl)-4-thiazolidinone derivatives as potent antitumor growth and metastasis agents | |
| JP2014511395A (en) | PI3 kinase inhibitors and uses thereof | |
| Ibrar et al. | New prospects for the development of selective inhibitors of α-glucosidase based on coumarin-iminothiazolidinone hybrids: Synthesis, in-vitro biological screening and molecular docking analysis | |
| US20140073668A1 (en) | N-quinolin-benzensulfonamides and related compounds for the treatment of cancer, autoimmune disorders and inflammation | |
| CA3140029A1 (en) | Tl1a patient selection methods, systems, and devices | |
| Li et al. | Novel naphtho [2, 1-d] oxazole-4, 5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation | |
| Baharudin et al. | Synthesis of indole analogs as potent β-glucuronidase inhibitors | |
| CN101801401A (en) | Kinase protein binding inhibitors | |
| Wang et al. | A novel ferulic acid derivative attenuates myocardial cell hypoxia reoxygenation injury through a succinate dehydrogenase dependent antioxidant mechanism | |
| Raghu et al. | Design, synthesis and molecular docking studies of imidazole and benzimidazole linked ethionamide derivatives as inhibitors of InhA and antituberculosis agents | |
| CN101232901B (en) | Joint use of sulfonamide based compound with angiogenesis inhibitor | |
| Ghorab et al. | Novel thioureido-benzenesulfonamide derivatives with enaminone linker as potent anticancer, radiosensitizers and VEGFR2 inhibitors | |
| CA3218004A1 (en) | Methods of treating cancers having a biallelic loss of function or gene overexpression mutation | |
| Yu et al. | Discovery of novel 9H-purin derivatives as dual inhibitors of HDAC1 and CDK2 | |
| TW200810758A (en) | Potentiator of radiation therapy | |
| Xiang et al. | Design, synthesis and antiproliferative activity evaluation of a series of pyrrolo [2, 1-f][1, 2, 4] triazine derivatives | |
| JP7364154B2 (en) | Selective PARP1 inhibitors to treat cancer | |
| Vanjare et al. | Elastase inhibitory activity of quinoline Analogues: Synthesis, kinetic mechanism, cytotoxicity, chemoinformatics and molecular docking studies | |
| CN111249283A (en) | Pyrimidine derivatives having anticancer effect | |
| Taha et al. | Synthesis: Small library of hybrid scaffolds of benzothiazole having hydrazone and evaluation of their β-glucuronidase activity | |
| CN105726544B (en) | A kind of anticancer usage of small molecular organic compounds FN-01 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |