CN106565643A - D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof - Google Patents
D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof Download PDFInfo
- Publication number
- CN106565643A CN106565643A CN201610927685.3A CN201610927685A CN106565643A CN 106565643 A CN106565643 A CN 106565643A CN 201610927685 A CN201610927685 A CN 201610927685A CN 106565643 A CN106565643 A CN 106565643A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- substituted
- halogen
- formula
- 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.)
- Pending
Links
- 0 CO*(c1ccc(C(*)=O)[o]1)OC Chemical compound CO*(c1ccc(C(*)=O)[o]1)OC 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention discloses a D-3-phosophoglycerate dehydrogenase allosteric inhibitor and an application thereof. The structure of the D-3-phosophoglycerate dehydrogenase allosteric inhibitor is shown in a formula I defined in the specification, wherein R1, R2 and R3 are same or different, and each of R1, R2 and R3 independently represents hydrogen, halogen, nitryl, hydroxyl, amino, carboxyl, alkyl, alkoxy, halogen substituted alkyl, carboxylic acid ester, sulphonylamino, acylamino or N-alkyl substituted acylamino, or two adjacent substituent groups are cyclized; R4 represents alkyl, halogen substituted alkyl, amino, cycloalkyl, aryl or substituted aryl; and X is O, N or S. Through an in-vitro enzyme activity test and a cell activity test, it is proved that a compound can specifically inhibit the activity of a D-3-phosophoglycerate dehydrogenase, and inhibit cancer cell growth. The compound is applied separately or is combined with other anti-cancer drugs to be applied, and can treat, prevent or inhibit tumor diseases such as breast cancers, colon cancers, melanin tumors, non-small cell lung cancers and the like.
Description
Technical field
The present invention relates to treat and prevent due to the medicine of the disorderly caused various diseases of serine metabolism, more particularly to make
For a class compound of D-3- phosphoglycerate dehydrogenase inhibitor, and the compound and combinations thereof medication is in treatment mammary gland
Application in cancer, colon cancer, melanoma, nonsmall-cell lung cancer and Other diseases.
Background technology
D-3- phosphoglycerate dehydrogenases (PHGDH) the catalytic serine synthesis first step in human body, is serine synthesis
Key enzyme in path.PHGDH was proved the melanoma cell in the mankind 40% or 70% three negative breasts in 2011
There is the situation of overexpression in cancerous cell etc., the knockout experiment for carrying out PHGDH genes finds that these cancerous cell are in vivo and in vitro
Growth be largely suppressed【(1)Locasale,J.W.,Grassian,A.R.,Melman,T.,Lyssiotis,C.A.,
Mattaini,K.R.,Bass,A.J.,Heffron,G.,Metallo,C.M.,Muranen,T.,Sharfi,H.,et al.
(2011).Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes
to oncogenesis.Nat.Genet.43,869-874.(2)Possemato,R.,Marks,K.M.,Shaul,Y.D.,
Pacold,M.E.,Kim,D.,Birsoy,K.,Sethumadhavan,S.,Woo,H.K.,Jang,H.G.,Jha,A.K.,et
al.(2011).Functional genomics reveal that the serine synthesis pathway is
essential in breast cancer.Nature 476,346-350.】.Therefore, carried out as anticancer target using PHGDH
Drug design has bright prospects.Due to PHGDH active pocket small volumes, prothetic group NAD+In vivo at concentrations up to
0.3mM and PHGDH complete crystal structures such as do not solve so far at the reason, and the drug design based on PHGDH active pockets enters to postpone
Slowly.New thinking is to carry out the allosteric control of PHGDH, designs the inhibitor of PHGDH.
Allosteric control in protein can be described as other structure molecule combine cause albumen in the nonactive site of albumen
The phenomenon that activity changes.The advantage of other structure medicine is that it has high specificity, and regulation and control target proteinses are active rather than complete
Its loss of activity is made entirely, and it plays effect etc. in the presence of endogenous ligands.
There is document to point out:The combination such as the knockout of PHGDH genes and cancer therapy drug cisplatin, amycin can show in vivo and in vitro
Write improve cancer therapy drug biological activity [(3) Jing, Z., Heng, W., Xia, L., Ning, W., Yafei, Q., Yao, Z.,
and Shulan,Z.(2015)Downregulation of phosphoglycerate dehydrogenase inhibits
proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma
cells by regulating Bcl-2and caspase-3,Cancer Biol.Ther.16,541-548.(4)Zhang,
X.,and Bai,W.(2016)Repression of phosphoglycerate dehydrogenase sensitizes
triple-negative breast cancer to doxorubicin,Cancer Chemother.Pharmacol.78,
655-659.), this is used there is provided reference to carry out PHGDH inhibitor with anti-cancer agent in combination.So far, PHGDH is had no
Inhibitor enters the report of clinical research, also has no that it is reported with the effect of drugs that anti-cancer agent in combination is used.For PHGDH
Other structure site is carried out drug design and allosteric inbibitor is used for into tumor prevention and treatment, with novelty and creativeness.
The content of the invention
It is an object of the invention to provide a class can be used as compound of allosteric inbibitor of PHGDH and preparation method thereof.
The present invention also aims to provide above-claimed cpd treat and prevent some breast carcinoma, colon cancer, black preparing
Application in the disease medicament such as melanoma and nonsmall-cell lung cancer.
The present invention also aims to provide above-claimed cpd exist with other PHGDH inhibitor or cancer therapy drug composite reagent
Prepare the application treated and prevented in the disease medicaments such as some breast carcinoma, colon cancer, melanoma and nonsmall-cell lung cancer.
The present invention is by PHGDH protein surface property analysis, being found suitable for the potential other structure site (ginseng of small molecule combination
See Fig. 1), and carried out virtual screening for institute's prediction bits point.Then new compound is designed and synthesized, and by external enzyme activity
Property test and cytoactive test confirm, the present invention provide compound be PHGDH inhibitor.
What the present invention was provided can have following general structure as the compound of the allosteric inbibitor of PHGDH:
In Formulas I, R1、R2、R3It is identical or different, each independently represent hydrogen, halogen, nitro, hydroxyl, amino, carboxyl, alkyl,
Alkoxyl, halogen-substituted alkyl, carboxylic acid ester groups, sulfoamido, amide groups or N- alkyl substituted amide bases, or it is wherein adjacent
Two substituent group (R1And R2Or R2And R3) cyclization;R4Represent alkyl, halogen-substituted alkyl, amino, cycloalkyl, unsubstituted or take
For aryl;X is O, N or S.
The halogen includes F, Cl, Br and I.
Work as R1、R2And R3In one or more when being alkyl, preferably C1~C12 alkyl, more preferably C1~C6 alkane
Base, such as methyl, ethyl, propyl group, isopropyl etc.;For alkoxyl when, preferably C1~C8 alkoxyls, more preferably C1~C4 alkane
Epoxide, such as methoxyl group, ethyoxyl, propoxyl group etc.;For halogen-substituted alkyl when, the preferably C1 of one or more halogen substiuteds
C1~C6 alkyl of~C12 alkyl, more preferably one or more halogen substiuteds, is often fluorine replacement, such as trifluoromethyl.
Work as R1、R2And R3In one or more be the carboxylic acid ester groups when, preferably C1~C8 esters epoxide (-
COOCnH2n+1, n is 1~7 integer), more preferably C1~C4 esters epoxide, such as methoxy ester group, ethoxy ester group, isopropyl oxygen ester group
Deng.
Work as R1、R2And R3In one or more be the N- alkyl substituted amides base when, preferably C1~C12 alkyl takes
The alkyl-substituted amide groups of the amide groups in generation, more preferably C1~C6, such as N- methyl acylaminos, N, N- dimethyl acylaminos
Deng.
Work as R1And R2Or R2And R3During cyclization, adjacent two substituent group Joint Representative 1,3-butadiene-Isosorbide-5-Nitrae-subunits,
1,4- dibutyl etc..
Work as R4For alkyl when, preferably C1~C12 alkyl, more preferably C1~C6 alkyl, such as methyl, ethyl, propyl group,
Isopropyl etc..
Work as R4For halogen-substituted alkyl when, preferably C1~C12 alkyl of one or more halogen substiuteds, more preferably one
C1~C6 alkyl of individual or multiple halogen substiuteds, such as trifluoromethyl etc..
Work as R4For cycloalkyl when, preferably C5~C7 cycloalkyl, such as cyclohexyl.
Work as R4For unsubstituted or substituted aryl when, the aryl is preferably phenyl, and the substituted aryl is more preferably 4- and takes
The phenyl in generation, the substituent group on phenyl is preferably C1~C6 alkyl, C1~C6 alkyl of halogen substiuted, nitro, C1~C4 alcoxyls
Base etc., such as 4- trifluoromethyls, 4- nitrobenzophenones.
Particularly, compound of formula I of the present invention does not include 10 particular compounds set forth below:
Above-mentioned compound of formula I can be prepared by multistep organic synthesiss, with 5-bromofuran-2-carboxaldehyde (or 5- formoxyl furans
Mutter -2- boric acid or 5- bromothiophene -2- formaldehyde) for initiation material, first prepare the five-ring heterocycles aldehyde intermediate of phenyl replacement, then with taking
For the five-ring heterocycles aldehyde reaction that thiosemicarbazides and phenyl replace, Jing multistep organic synthesiss obtain the inhibitor shown in Formulas I.
Other specific examples of compound of formula I are referring to the table 1 in embodiment 2.
Chemical substance used by this synthetic route is commercially available prod or can be obtained by prior art synthesis, reacted
When, the operational approach for being adopted and operating procedure and reaction condition and intermediate etc. are in accordance with those skilled in the art ripe
The methodology of organic synthesis design known, implement, and be disclosed in embodiment.
The present invention confirms that the compound shown in Formulas I can specificity suppression by the test of external enzyme activity, cytoactive test experiments
PHGDH processed is active.PHGDH is suppressed by the other structure of compound of formula I, it is possible to decrease overexpression of the PHGDH in cancerous cell, so as to suppress
The growth of cancerous cell.
By the compound of formula I of the present invention individually, or with other PHGDH inhibitor or cancer therapy drug composite reagent, or
Using their pharmaceutical salts as effective ingredient, add Conventional pharmaceutical carriers, the medicine for treating or preventing various cancers can be prepared
Thing.
The pharmaceutical salts of compound of formula I and combinations thereof the medication of the present invention refer to pharmaceutically acceptable salt, for example with hydrochloric acid,
The mineral acids such as sulphuric acid, phosphoric acid, nitric acid formed salt, or with citric acid, succinic acid, citric acid, acetic acid, tartaric acid, methanesulfonic acid
Deng the salt that organic acid is formed.
Conventional pharmaceutical carriers refer to nontoxic solid-state, semisolid or liquid filler, diluent, adjuvant, lapping or other
Pharmaceutical adjunct.According to techniques known, can according to therapeutic purposes, route of administration need pharmaceutical composition is made
Various dosage forms.
Description of the drawings
Fig. 1 shows the other structure site of the PHGDH that protein surface property locator CAVITY is predicted.
Fig. 2 is the molecular docking figure of compound PKUMDL-PG-001 (A) and PKUMDL-PG-021 (B) and PHGDH.
Specific embodiment
Following examples are used to illustrate the present invention that the method for the present invention to be put into practice in expression, and it is to the scope of the present invention without any
Limit.Those skilled in the art may find the obvious additive method for realizing the present invention for them, all should recognize
It is included in the scope of the present invention for those methods.
The discovery of embodiment 1, PHGDH allosteric inbibitors
First, the prediction in the other structure sites of PHGDH
PHGDH(PDB code:2G76) the prediction in other structure site, uses protein surface heuristic routine CAVITY.It is first
First, the program is detected by wiping ball method to protein surface, finds the potential binding site of protein surface;Subsequently, journey
Sequence rule of thumb formula (CavityScore=(Volume-AdjustVolume)/(SurfaceArea-
AdjustSurfaceArea)) ability of protein binding small molecule is given a mark.AdjustVolume and
AdjustSurfaceArea is related to the hydrophobic area of residue and hydrogen bond receptor donor quantity in predicted site.By to known
The maximum pK of binding site-ligand binding pairDGiven a mark, and with known experiment pKDValue is fitted, and obtains preferably linear
Dependency.Therefore, binding site-part maximum pK that program can will give a mark to predict according to above-mentioned formulaDThe form of value is given.
According to pKDNumerical value and pocket volume size, it is final to choose suitable potential other structure site.For PHGDH, we are first
It is secondary to obtain two brand-new potential other structure sites, MDL-1 and MDL-2.As shown in figure 1, MDL-1 be located at avtive spot with
And prothetic group NAD+The vicinity of binding site, pocket volume isThe maximum pK for being predictedDFor 8.71.MDL-2 is located at substrate
Binding structural domain, pocket volume size isThe maximum pK for being predictedDFor 7.79.The object of study of the present invention is MDL-
2。
2nd, the virtual screening of the other structure molecules of PHGDH
For the other structure site predicted, using the method for molecular docking, to the SPECS data comprising about 200,000 compounds
Storehouse carries out virtual screening.First, rough rigidity docking is carried out using Glide SP patterns, secondly, chooses marking front 10,000
Compound, it is considered to compound and protein residues side chain flexibility, further docked using Glide XP patterns.Finally,
The compound for choosing Glide XP marking front 1000 is reference, designs and synthesizes new compound for experimental verification.These changes
Compound further verifies activity during in vitro enzymatic activity is tested.
The synthesis of embodiment 2, other structure molecule
First, the design of other structure molecule
Fig. 2 shows that the other structure molecule of design and PHGDH's docks result.As can be seen from Figure 2A, compound (E) -4-
The phase interaction of (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzoic acid (numbering is PKUMDL-PG-001) and PHGDH
Use pattern:2- benzofurane aromatic rings occupy the hydrophobic cavity in pocket, and 4 carboxyl oxygens can form hydrogen with 59 threonine in phenyl ring
Key;NH in the hydrazine of thio formyl two2And one of NH groups can form hydrogen bond with 12 aspartic acids.Can be with from Fig. 2 B
Find out, compounds methyl (E) -4- (5- ((2- (ethylaminocarbonyl) hydrazono-) methyl) thiophene -2- bases) essence of Niobe
The Interactions Mode of (numbering is PKUMDL-PG-021) and PHGDH:2- tolylthiophene aromatic rings occupy the hydrophobic sky in pocket
Chamber, one of NH groups can form hydrogen bond with 12 aspartic acids in thiosemicarbazide group, and another NH group can be with 11
Serine forms hydrogen bond, and the N in imines then can form hydrogen bond with 35 leucines, while phenyl ring can form thin with hydrophobic residue
Water is acted on.
2nd, the synthesis of other structure molecule
Below citing describes the synthetic method of PHGDH inhibitor molecules of the present invention.
1. PKUMDL-PG-002
Synthetic route:
Experimental procedure:
(1) by 4- Carboxybenzeneboronic acids (0.546g, 3.23mmol), 5-bromofuran-2-carboxaldehyde (0.480g, 2.74mmol), TBAB
(0.615g,2.74mmol),Pd(OAc)2(0.007g, 0.03mmol) and Na2CO3(0.581g, 5.48mmol) is added to
In 250mL round-bottomed flasks, 100mL water is added.It is stirred at room temperature under protecting under Ar, TLC is detected to 5-bromofuran-2-carboxaldehyde raw material point and disappeared
Lose.Extracted with 50mL × 3 ethyl acetate, water is added to 3N HCl acidifyings, produces white precipitate.Filter, collect solid, dry
To 4- (5- formylfuran -2- bases) benzoic acid (0.414g, white solid, 70%).1H NMR(400MHz,DMSO-d6)δ
13.14 (s, 1H), 9.66 (s, 1H), 8.06 (d, J=8.4Hz, 2H), 8.00 (d, J=8.3Hz, 2H), 7.70 (d, J=
3.8Hz, 1H), 7.46 (d, J=3.8Hz, 1H).
(2) 4- (5- formylfuran -2- bases) benzoic acid (0.250g, 1.16mmol) that will be prepared, EDCI (0.265g,
1.39mmol), DMAP (0.07g, 0.058mmol) is dissolved in 25mL anhydrous tetrahydro furans, is added thereto to 2ml absolute methanols,
TLC detects complete to 4- (5- formylfuran -2- bases) benzoic acid.Solvent is spin-dried for, using silica gel column chromatography mesh is obtained
Mark product 4- (5- formoxyl -2- furyls) essence of Niobe.(0.227g, white solid, 85%).1H NMR(400MHz,
DMSO-d6) δ 9.66 (s, 1H), 8.08 (d, J=8.7Hz, 2H), 8.02 (d, J=8.6Hz, 2H), 7.70 (d, J=3.8Hz,
1H), 7.48 (d, J=3.8Hz, 1H), 3.89 (s, 3H).
(3) by thiocarbohydrazide (0.500g, 4.72mmol) be dissolved into 50ml 1,4- dioxane and water (volume ratio=
1:1) in mixed solution, 90 DEG C are heated to, be added thereto to 4- (5- formoxyl -2- furyls) essence of Niobe (0.050g,
0.2mmol).After TLC detection reactions completely, solvent is spin-dried for, then is added thereto to 20ml hot water.Filtered while hot, filter cake heat
Water washing.Purification obtains target compound methyl (E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzoic acid
Methyl ester 0.035g.(yellow solid, fusing point:179-181 DEG C, yield:55%).1H NMR(400MHz,DMSO-d6)δ11.56(s,
1H), 9.67 (s, 1H), 8.07-7.91 (m, 5H), 7.31 (d, J=3.6Hz, 1H), 7.14 (d, J=3.7Hz, 1H), 3.87
(s,3H);13C NMR(101MHz,DMSO-d6)δ176.14,166.26,153.49,150.79,134.10,131.80,
130.30,128.90,124.38,115.35,111.28,52.67.
PKUMDL-PG-001, PKUMDL-PG-003~008, PKUMDL-PG-022 etc. 8 is prepared for using similar approach
Compound.
2. PKUMDL-PG-009
Synthetic route:
Experimental procedure:
(1) will to methyl iodobenzene (0.974g, 4.47mmol), 5- formylfuran -2- boric acid (0.750g,
5.36mmol), TBAB (1.441g, 4.47mmol), Pd (OAc)2(0.050g, 0.22mmol) and Na2CO3(1.184g,
In 11.2mmol) being added to 250mL round-bottomed flasks, 100mL water is added.It is stirred at room temperature under protecting under Ar, TLC is detected to 5-
Bromo- 2- furfurals raw material point disappears.Solid is collected by filtration, is purified with silica gel column chromatography, obtain 5- (p-methylphenyl) furan -2- formaldehyde
(1.211g, yellow solid, 63%).1H NMR(400MHz,DMSO-d6):δ 9.59 (s, 1H), 7.78 (d, J=8.2Hz, 2H),
7.64 (d, J=3.8Hz, 1H), 7.33 (d, J=8.0Hz, 2H), 7.24 (d, J=3.8Hz, 1H), 2.36 (s, 3H).
(2) it is slow in methanol (100mL) solution of ethyl isothiocyanate (1.378g, 15.8mmol) under ice bath
The hydrazine hydrate (0.931g, 15.8mmol) of Deca 85%, about 15min completion of dropping continues that 3h is stirred at room temperature.Removed under reduced pressure is molten
Agent, with the pure crystallization of methanol, obtain 4- ethyl -3- thiosemicarbazides (0.856g, white solid, 45%).1H NMR(400MHz,
DMSO-d6):δ 8.53 (s, 1H), 7.81 (s, 1H), 4.42 (s, 2H), 3.47 (td, J=7.2,5.9Hz, 2H), 1.07 (t, J
=7.1Hz, 3H).
(3) by 5- (p-methylphenyl) furan -2- formaldehyde (0.100g, 0.4mmol) of step (1) and the 4- second of step (2)
Base -3- thiosemicarbazides (0.074g, 0.40mmol) is stirred at room temperature reaction in 20mL methanol solutions, and TLC is detected to raw material and disappeared
Lose.Vacuum distillation is gone out solvent, residue recrystallizing methanol, and ((5- is (to toluene to obtain target product (E)-N- ethyls -2-
Base) furan -2- bases) methylene) hydrazine thioformamide 0.097g (yellow solid, fusing point:185-187 DEG C, yield:85%).1H-
NMR(DMSO):δ 11.46 (s, 1H), 8.30 (t, J=6.0Hz, 1H), 7.97 (s, 1H), 7.72 (d, J=8.2Hz, 2H),
7.27 (d, J=8.0Hz, 2H), 7.05 (q, J=3.6Hz, 2H), 3.69-3.52 (m, 2H), 2.34 (s, 3H), 1.16 (t, J=
7.1Hz,3H);13C NMR(101MHz,DMSO-d6)δ176.79,155.24,149.12,138.27,132.20,129.98,
127.34,124.43,115.82,108.11,38.77,21.39,15.08.
12 compounds such as PKUMDL-PG-010~PKUMDL-PG-021 are prepared using similar approach.
Synthesized compound name is as follows:
PKUMDL-PG-001:(E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzoic acid;
PKUMDL-PG-002:Methyl (E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzoic acid first
Ester;
PKUMDL-PG-003:Ethyl (E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzoic acid first
Ester;
PKUMDL-PG-004:Isopropyl (E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzoic acid first
Ester;
PKUMDL-PG-005:Methyl (E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) -3- methylbenzene
Methyl formate;
PKUMDL-PG-006:Methyl (E) -2- amino -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzene
Methyl formate;
PKUMDL-PG-007:(E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases) benzsulfamide;
PKUMDL-PG-008:(E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) furan -2- bases)-N- toluyls
Amine;
PKUMDL-PG-009:(E)-N- ethyls -2- ((5- (p-methylphenyl) furan -2- bases) methylene) the thio formyl of hydrazine
Amine;
PKUMDL-PG-010:(E)-N- ethyls -2- ((5- (4- fluorophenyls) furan -2- bases) methylene) the thio formyl of hydrazine
Amine;
PKUMDL-PG-011:(E) -2- ((5- (4- bromophenyls) furan -2- bases) methyl) the thio first of-N- ethyl diazanyl -1-
Amide;
PKUMDL-PG-012:(E)-N- ethyls -2- ((5- (4- hydroxy phenyls) furan -2- bases) methylene) the thio first of hydrazine
Amide;
PKUMDL-PG-013:(E)-N- ethyls -2- ((5- (4- (trifluoromethyl) phenyl) furan -2- bases) methylene) hydrazine
Thioformamide;
PKUMDL-PG-014:(E)-N- ethyls -2- ((5- (naphthalene -1- bases) furan -2- bases) methylene) the thio formyl of hydrazine
Amine;
PKUMDL-PG-015:(E)-N- ethyls -2- ((5- (4- methoxyphenyls) furan -2- bases) methylene) diazanyl -1-
Thioformamide;
PKUMDL-PG-016:(E) the chloro- 5- of -2- (5- ((2- (ethylaminocarbonyl) hydrazono-) methyl) furan -2-
Base) benzoic acid;
PKUMDL-PG-017:Methyl (E) -4- (5- ((2- (ethylaminocarbonyl) hydrazono-) methyl) furan -2- bases)
Essence of Niobe;
PKUMDL-PG-018:(E) -4- (5- ((2- (cyclohexyl phosphinylidyne) diazanyl) methyl) furan -2- bases) benzoic acid;
PKUMDL-PG-019:(E) -4- (5- ((2- ((4- (trifluoromethyl) phenyl) phosphinylidyne) diazanyl) methyl) furan -2-
Base) benzoic acid;
PKUMDL-PG-020:Methyl (E) -4- (5- ((2- ((4- nitrobenzophenones) phosphinylidyne) diazanyl) methyl) furan -2- bases)
Essence of Niobe;
PKUMDL-PG-021:Methyl (E) -4- (5- ((2- (ethylaminocarbonyl) hydrazono-) methyl) thiophene -2- bases)
Essence of Niobe;
PKUMDL-PG-022:Methyl (E) -4- (5- ((2- (hydrazine carbonyl) hydrazono-) methyl) thiophene -2- bases) benzoic acid first
Ester.
The characterize data row of above-claimed cpd are shown in Table 1, nmr spectrum data (1H-NMR) by U.S. Varian
Mercury 400M are measured.Using containing tetramethylsilane be interior target deuterated dimethyl sulfoxide as solvent, coupling constant with
Used as unit, abbreviation used is illustrated as Hz:S=is unimodal, and d=is bimodal, t=triplets, q=quartets, m=multiplets, br=
Single broad peak.High resolution mass spectrum data (HRMS) is measured by U.S.'s Brsucker Apex IV FTICRMS instruments.Fusing point is by Beijing
Tyke Instrument Ltd. X-4 numerical monitor micro melting point apparatus are measured.
The characterization of compound of table 1.
Embodiment 3, fluorescence kinetics method determine impact of the other structure molecule to the external enzymatic activitys of PHGDH
The measure of PHGDH enzymatic activitys is realized by detecting fluorescence emission spectrums of the NADH at 456nm.First,
PHGDH (final concentration 30ng/ μ L) in 96 orifice plates with HEPES buffer solution (25mM, pH 7.1,400mM KCl), 5 μM of PLP,
0.5mM α KG, 150 μM of NADH and PSAT1 (final concentration 30ng/ μ L) are incubated 10 minutes.Subsequently, 10 μ L DMSO (controls are added
Group) or the DMSO solution containing small molecule, balance is shaken 5 minutes with the rotating speed of 550rpm at 25 DEG C.Enzyme activity body test system
The final concentration (v/v) of middle holding DMSO is 5%.Finally, add Pser aqueous solutions (final concentration 0.5mM), start reaction, and with purple
Outer visible microplate reader monitors the consumption of NADH under 456nm over time.Albumen is lived using first rate is reacted within 30s
Property be estimated, now NADH is consumed and is increased linear with the time.Test result is shown in Table 2.
The vitro enzyme active testing result of table 2.
The dose-effect relationship of further investigation compound, obtains the IC of 8 compounds50Numerical value, the activity of PKUMDL-PG-002 is most
It is high.
The cancer cell suppression activity of embodiment 4, other structure molecule
From a series of cancerous cell and normal mammary epithelial, using MTT (3- (and 4,5)-
Dimethylthiahiazo (- z-y1) -3,5-di-phenytetrazoliumromide) experimental technique, compound is existed
Biological activity on cellular level is studied.Specific practice is:First, by the PHGDH sensitivities in exponential phase growth
Breast cancer cell MDA-MB-468 (5000 cells/well) and PHGDH insensitive Human breast cancer cells ZR-75-1 (4000 cells/
Hole) it is transferred to 96 orifice plates, it is overnight adherent.Then, the compound of addition variable concentrations is little with cell incubation 72 into 96 orifice plates
When, control DMSO final concentrations (v/v) is 0.2%.DMSO without any compound is used as control.Subsequently, after 72 hours, to each
Add 20 μ L 5mg/mL MTT, after being incubated at least 4 hours, remove the liquid in each experimental port in individual experimental port, add 200 μ L
DMSO, 37 DEG C are slowly rocked 10 minutes, using microplate reader detect 490nm at can be with light absorbs.Experimental data is deposited using cell
Motility rate % representing, cell median lethal rate EC50Value is obtained by Hill equation models.
PKUMDL-PG-020, PKUMDL-PG-021 show on a cellular level micromolar killing activity and (are shown in Table
3).These compounds show PHGDH sensitive breast cancer cell MDA-MB-468 more than 10 times of cell selective.
PKUMDL-PG-001 then goes out the activity of the cell-lethal without concentration dependant, and PKUMDL-WQL- to MDA-MB-468 cells shows
019 does not obtain cell-lethal activity because dissolubility is poor.
The cancer cell suppression activity of table 3.
Claims (10)
1. compound of formula I:
In Formulas I, R1、R2、R3It is identical or different, each independently represent hydrogen, halogen, nitro, hydroxyl, amino, carboxyl, alkyl, alcoxyl
Base, halogen-substituted alkyl, carboxylic acid ester groups, sulfoamido, amide groups or N- alkyl substituted amide bases, or wherein adjacent two
Substituent group cyclization;R4Represent alkyl, halogen-substituted alkyl, amino, cycloalkyl, aryl or substituted aryl;X is O, N or S;And under
Except 10 compounds listed by face:
2. compound of formula I as claimed in claim 1, it is characterised in that work as R1、R2And R3In one or more be alkyl when,
The alkyl is C1~C12 alkyl;Work as R1、R2And R3In one or more be alkoxyl when, the alkoxyl be C1~C8 alkane
Epoxide;Work as R1、R2And R3In one or more be halogen-substituted alkyl when, the halogen-substituted alkyl be one or more halogen
C1~C12 alkyl that element replaces;Work as R1、R2And R3In one or more be carboxylic acid ester groups when, the carboxylic acid ester groups be C1~C8
Ester epoxide;Work as R1、R2And R3In one or more be N- alkyl substituted amide bases when, the N- alkyl substituted amides base be C1
The alkyl-substituted amide groups of~C12.
3. compound of formula I as claimed in claim 1, it is characterised in that work as R1And R2Or R2And R3During cyclization, adjacent two
Substituent group Joint Representative 1,3- butadiene subunit or 1,4- dibutyl.
4. compound of formula I as claimed in claim 1, it is characterised in that work as R4For alkyl when, the alkyl be C1~C12 alkane
Base;Work as R4For halogen-substituted alkyl when, the halogen-substituted alkyl is C1~C12 alkyl of one or more halogen substiuteds;Work as R4
For cycloalkyl when, the cycloalkyl be C5~C7 cycloalkyl;Work as R4For aryl or substituted aryl when, the aryl be phenyl, institute
Substituted aryl is stated for substituted-phenyl.
5. compound of formula I as claimed in claim 4, it is characterised in that the substituted-phenyl is the phenyl that 4- replaces, on phenyl
Substituent group be C1~C6 alkyl, C1~C6 alkyl of halogen substiuted, nitro or C1~C4 alkoxyls.
6. compound of formula I as claimed in claim 1, it is characterised in that compound shown in the Formulas I is following compounds
One of PKUMDL-PG-001 to PKUMDL-PG-022:
7. in claim 1~6 compound of formula I described in any one preparation method, shown in following reaction equation:
With 5-bromofuran-2-carboxaldehyde, or 5- formylfuran -2- boric acid, or 5- bromothiophene -2- formaldehyde is initiation material, first prepares benzene
The five-ring heterocycles aldehyde intermediate that base replaces, then the five-ring heterocycles aldehyde reaction replaced with substituted-amino thiourea and the phenyl, synthesize
To compound of formula I, wherein R1、R2、R3、R4With X as described in the appended claim 1.
8. the compound of formula I and its pharmaceutical salts in claim 1~6 described in any one is being prepared for treating, preventing or pressing down
Purposes in the medicine of tumor processed.
9. purposes as claimed in claim 8, it is characterised in that the tumor is breast carcinoma, colon cancer, melanoma or non-little
Cell lung cancer.
10. the compound of formula I and its pharmaceutical salts in claim 1~6 described in any one takes off in preparation D-3- phosphoglyceric acids
Application in the inhibitor of hydrogen enzyme.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610927685.3A CN106565643A (en) | 2016-10-31 | 2016-10-31 | D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610927685.3A CN106565643A (en) | 2016-10-31 | 2016-10-31 | D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN106565643A true CN106565643A (en) | 2017-04-19 |
Family
ID=60414401
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610927685.3A Pending CN106565643A (en) | 2016-10-31 | 2016-10-31 | D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106565643A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018076537A1 (en) * | 2016-10-31 | 2018-05-03 | 北京大学 | D-3-phosphoglycerate dehydrogenase allosteric inhibitor and use thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004060308A2 (en) * | 2002-12-27 | 2004-07-22 | Chiron Corporation | Thiosemicarbazones as anti-virals and immunopotentiators |
WO2011072275A2 (en) * | 2009-12-11 | 2011-06-16 | Nono, Inc. | Agents and methods for treating ischemic and other diseases |
CN106562951A (en) * | 2016-10-31 | 2017-04-19 | 北京大学 | Furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof |
-
2016
- 2016-10-31 CN CN201610927685.3A patent/CN106565643A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004060308A2 (en) * | 2002-12-27 | 2004-07-22 | Chiron Corporation | Thiosemicarbazones as anti-virals and immunopotentiators |
WO2011072275A2 (en) * | 2009-12-11 | 2011-06-16 | Nono, Inc. | Agents and methods for treating ischemic and other diseases |
CN106562951A (en) * | 2016-10-31 | 2017-04-19 | 北京大学 | Furan D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof |
Non-Patent Citations (8)
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018076537A1 (en) * | 2016-10-31 | 2018-05-03 | 北京大学 | D-3-phosphoglycerate dehydrogenase allosteric inhibitor and use thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Krasavin et al. | Continued exploration of 1, 2, 4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment | |
Grandane et al. | 6-Substituted sulfocoumarins are selective carbonic anhdydrase IX and XII inhibitors with significant cytotoxicity against colorectal cancer cells | |
Hameed et al. | Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors | |
CN104080455B (en) | Certain chemical entities, composition and method | |
CN107922425B (en) | Methods of preparing PARP inhibitors, crystalline forms and uses thereof | |
CN1807413B (en) | Carbazole sulfonamide derivative and its preparation method | |
US11370770B2 (en) | 3-arylindazoles as selective MEK4 inhibitors | |
CN103848829B (en) | Heteroaryl alkyne compounds and application thereof | |
Yang et al. | Discovery of 2-((4, 6-dimethylpyrimidin-2-yl) thio)-N-phenylacetamide derivatives as new potent and selective human sirtuin 2 inhibitors | |
Zhao et al. | Discovery of meta-sulfamoyl N-hydroxybenzamides as HDAC8 selective inhibitors | |
Doğan et al. | Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors | |
Cheng et al. | Discovery of novel cyclin-dependent kinase (CDK) and histone deacetylase (HDAC) dual inhibitors with potent in vitro and in vivo anticancer activity | |
Abbas et al. | Synthesis and in vitro urease inhibitory activity of benzohydrazide derivatives, in silico and kinetic studies | |
KR102214225B1 (en) | 5-membered heterocyclic amide type WNT pathway inhibitor | |
KR20210053911A (en) | Heterocyclic compounds as AHR modulators | |
ES2308916A1 (en) | Compound that is a dual inhibitor of enzymes pde7 and/or pde4, pharmaceutical compositions and uses thereof | |
Lan et al. | Chromanones: selective and reversible monoamine oxidase B inhibitors with nanomolar potency | |
Gao et al. | The discovery of novel benzothiazinones as highly selective non-ATP competitive glycogen synthase kinase 3β inhibitors for the treatment of ovarian cancer | |
EP3284743B1 (en) | Heterocyclic-imidazole compounds, pharmaceutical compositions thereof, preparation method therefor and use thereof | |
Çapan et al. | Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as anticancer, and antioxidant agents | |
CN108774218A (en) | The pyrimidine anti-tumor compounds and its preparation method and application of 1,3,4- oxadiazoles structures | |
CN106565643A (en) | D-3-phosophoglycerate dehydrogenase allosteric inhibitor and application thereof | |
Naseem et al. | Therapeutic potential of 1, 3, 4-oxadiazoles as potential lead compounds for the treatment of Alzheimer's disease | |
JP2021510152A (en) | Compounds that simultaneously target and inhibit LSD1 and HDAC and their uses | |
Dong et al. | Design, synthesis and biological evaluation of exiguamine A analogues as IDO1 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170419 |
|
WD01 | Invention patent application deemed withdrawn after publication |