CN106432250A - Indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds with antitumor activity as well as preparation method and application of compounds - Google Patents
Indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds with antitumor activity as well as preparation method and application of compounds Download PDFInfo
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- CN106432250A CN106432250A CN201610808997.2A CN201610808997A CN106432250A CN 106432250 A CN106432250 A CN 106432250A CN 201610808997 A CN201610808997 A CN 201610808997A CN 106432250 A CN106432250 A CN 106432250A
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- Prior art keywords
- carbazole
- diketone
- pyrroles
- reaction
- indoles
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- 150000003584 thiosemicarbazones Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds with antitumor activity as well as a preparation method and an application of the compounds. The technical scheme is characterized in that the indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds with the antitumor activity are prepared from raw materials including substituent isothiocyanate compounds R-NCS and 6-amino-indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone shown in the specification and has a general structure formula shown in the specification. The invention further discloses the preparation method of the indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds with the antitumor activity and the application of the indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds with the antitumor activity in preparation of an antitumor drug. According to the preparation method, the raw materials are cheap and easy to obtain, the operation is simple, and the prepared indole [2,3-a] pyrrole[3,4-c] carbazole-5,7-diketone-6-thiosemicarbazone compounds have better biological activity and have better application prospect in preparation of an antitumor drug compound.
Description
Technical field
The invention belongs to there is the noval chemical compound synthesis technical field of active anticancer and in particular to one kind has active anticancer
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound and its preparation method and application.
Background technology
Bisindole maleimide derivative is that the class being designed for primer with Staurosporine has excellent activity
Alkaloid because with indole carbazole analog derivative synthesis on correlation, be therefore also included into indole carbazole compound.Yin
Diindyl carbazole core can be obtained by corresponding bisindole maleimide compound oxidation or illumination cyclization, Arcyriaflavia
Synthesis equation as follows[1].
Indoles simultaneously [2,3-a] carbazole compound earliest from rod spore streptomycete Streptomyces staurosporeus's
Separate in zymotic fluid and obtain, this natural alkaloid is named as staurosporin (staurosporine).X single crystal diffraction is analyzed
Show that it, by indoles [2,3- α] pyrrolo- [3,4-c] carbazole ring, is combined to form by two C-N keys and an amino pyranose
, its structural formula is as follows.Find within 1986 that this alkaloid has antimycotic, anti-hypertension, antitumor and suppression platelet aggregation
Deng effect[2], indole carbazole compound antitumor activity action target spot includes the multiple kinases relevant with the cell cycle, cell
Core topoisomerase (topoisomerase, Top) and the enzyme relevant with growth of tumour cell or apoptosis etc..Know indoles
Carbazole compound is the intoxicating agent of topoisomerase, and it shows to the inhibitory action of protein kinase (protein kinase)
Special amino acid group on competition binding its atriphos (ATP) pocket, and then the activity of inhibitory enzyme, and make cell growth
It is still in the G1 phase.
Indole carbazole compound at least show the three class modes of action in mammalian cell：Suppression protein kinase, suppression
Eukaryotic cell dna topoisomerase I processed and the Embedded combination with DNA.Protein kinase is a family, including multiple enzymes,
The phosphorylation of these enzymatic gal4 amino acid residues, task in the cell is to control multi-signal transduction.Send out through research
Existing staurosporin had both suppressed protein kinase C, also suppressed other protein kinases, although therefore this compound efficiently but albumen
The nonspecific inhibitor of kinases.Crystal structure display staurosporin is located at atriphos (ATP) binding site, Ren Heyi
Kind of indole carbazole inhibitor action site is not always the case, in the gap of two protease slivers indole carbazole occupy hydrophobic
Adenine binding pocket, lactam group forms two hydrogen bonds by the N- end of kinases and C- stub area, be in boat conformation and
Glycosyl perpendicular to indole carbazole ring has been internally formed hydrophobic connection and hydrogen bond in ribosomal binding sites.Staurosporin and three phosphorus
Adenosine monophosphate (ATP) binding site cooperation so tacit agreement, causes staurosporin activity very high, but comparatively its specificity is relatively
Low[3].
DNA topoisomerase is treatment tumour and the target for the treatment of bacterium, its participate in multiple separate with DNA double chain relevant
Cell processes, such as replicate, translate, recombinate and repair.Rebeccamycin can be in vitro via DNA topoisomerase I inducing DNA
Cracking, thus leading to cytotoxic and causing Apoptosis[4].Staurosporin then passes through to stop from DNA to active tyrosine position
Point shifts phosphodiester bond and suppresses the catalysis activity of Top II[5].By with the kinase inhibitor structure species having been found that
Diversity is compared, and has the indole carbazole significantly combining or topoisomerase I being risen with toxic action only with DNA and rebecca
The indole carbazole compound that mycin is similar to.
Because such indole carbazole compound has antibacterial, antiviral, anti-hypertension and many biologically actives such as antitumor.
Researcher starts just to have attracted a lot of biologists, chemist and pharmaceutical from discovery indole carbazole Alkaloid
The broad interest of company, by Separation of Natural Products, fully synthetic and synthesis to its derivative, such compound exceedes
Kind more than 100.Most is exactly the research of antitumor activity, has had the chemical combination with indole carbazole nuclear structure of document report
Thing, such as rebeccamycin analog[6]With staurosporine derivatives UCN-01, CEP-1347, NB-506, ED-571 and JDC-
108 etc.[7].Indole carbazole compound, especially staurosporine derivatives show different biologically actives, including fall blood
Pressure, suppression platelet aggregation, suppression smooth muscle contraction, activating macrophage, the prevention propagation to mitogen for the T lymphocyte
Reaction, suppression ion vitro immunization, suppression osteoclast proton pump, insecticidal activity, the reverse multidrug resistance to the action of a drug and neuroprotective etc.[8].
[1]Mahboobi S；Dechant I；Reindl H.et al.Synthesis of Bis
(indolylmaleimide)Macrocycles[J].Heterocycl.Chem.,2000,37:307-329.
[2]Omura S；Sasaki Y；Iwai Y.et al.J.Antibiotics,1995,48:535-548.
[3]Michael G；Christine B；Norbert K.et al.The protein kinase C
inhibitor bisindolyl maleimide 2binds with reversed orientations to different
conformations of protein kinaseA[J].The Journal of Biological Chemistry,2004,
279:23679-23690.
[4]Yuichi S.；Shyam B.；Mechanism of hydrolysis of a
novelindolocarbazole topoisomerase I inhibitor[J].European Journal of
Pharmaceutical Sciences,2010,39(5):291-297.
[5]Piotr L；Guyanand S；Robert K.Mechanism of topoisomerase II
inhibition by staurosporine and otherprotein kinase inhibitors[J].The Journal
of Biological Chemistry,1996,271；26418-26421.
[6] Zhang Guisheng；Wang Junqiang；Shi Junhong. there is rebeccamycin analog and the synthetic method [P] of active anticancer
.GB CN201010569632.1,2011-07-20.
[7] Chen Suting；Outstanding Qidong. the antitumor activity [J] of indole carbazole compound and its derivative. chemical progress,
2008,20(2/3):368-374.
[8]Hirofumi N.；Satoshi O.；Chemical biology of natural indolocarbazole
products:30years since the discovery of staurosporine[J].The journal of
antibiotics.,2009,62:16-26.
Content of the invention
It is an object of the invention to provide a kind of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- with active anticancer
Diketone -6- (thiosemicarbazone) compound and preparation method thereof, is to have synthesized a class using the principle of active fragment splicing newly to change
Compound, and its biologically active is analyzed, such noval chemical compound has active anticancer, can be used in preparing cancer therapy drug.
For achieving the above object, the present invention adopts the following technical scheme that：There is indoles [2,3-a] pyrroles of active anticancer
[3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound is it is characterised in that be to replace isosulfocyanate chemical combination
Thing R-NCS and 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketoneFor raw material
It is prepared from, its general structure is：Wherein R is
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- contracting ammonia with active anticancer of the present invention
The preparation method of base thiourea is it is characterised in that concrete synthesis step is：It is initially charged 6- amino-Yin in reaction vessel
Diindyl [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and ionic liquid BMIM BF4, it is subsequently adding replacement isosulfocyanate
Compound, reacts under 85 DEG C of counterflow conditions, and TLC follows the tracks of, and reaction is dried in the air after terminating to room temperature, and decompression boils off solvent, and column chromatography divides
From obtaining yellow solid indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound, specifically instead
The equation is answered to be：
Wherein replacing isosulfocyanate compound is one of structure set forth below：
Further preferably, described 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and the different sulphur of replacement
The molar ratio of cyanate compound is 1:1.2.
Further preferably, described 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone is by with lower section
Method is prepared from：
(1) synthesis of 2,3- dichloro maleic anhydride
Add maleic anhydride in reaction vessel, under condition of ice bath, add thionyl chloride, magnetic agitation uniformly, uses constant pressure addition
Funnel drips pyridine, after completion of dropping, continues stirring reaction under condition of ice bath, then removes ice bath, oil bath heating flows back, decompression
Boil off the thionyl chloride of residual, obtain yellow, waxy solid, then leached with toluene, suction filtration, obtain yellow filtrate, repeatedly count
The secondary whiting to solid, merging filtrate, decompression obtains crude product 2,3- dichloro maleic anhydride after boiling off solvent；
(2) synthesis of 2,3- Dichloro-N-methyl maleimide
2,3- dichloro maleic anhydride, methylamine hydrochloride and glacial acetic acid, magnetic agitation under counterflow condition is added in reaction vessel
Reaction, completely, solution is in crineous to TLC tracking and monitoring to raw material reaction, adds water after being down to room temperature, is extracted with ethyl acetate, according to
Secondary saturated sodium bicarbonate solution and saturated aqueous common salt clean, and decompression boils off solvent, obtains brown crude product, column chromatography for separation obtains
White flaky solid 2,3- Dichloro-N-methyl maleimide；
(3) synthesis of 2,3- bis- (3- indoles)-N- methylmaleimido
The preparation of a bromoethane RMgBr
N2Under protection, add magnesium rod and absolute ether in reaction vessel, and drip bromoethane, acute after low-grade fever initiation reaction
Strong stirring, dropping bromoethane makes solvent keep slight boiling condition, adds absolute ether, backflow reacts fully, and obtains after completion of dropping
To smoky gray bromoethane RMgBr,
The preparation of b indoles RMgBr and the preparation of 2,3- bis- (3- indoles)-N- methylmaleimido
To in reaction vessel, first add the toluene solution of oxolane, indoles and bromoethane RMgBr, solution turns black,
React in 40 DEG C, be subsequently adding the toluene solution of 2,3- Dichloro-N-methyl maleimide, completion of dropping, solution is in reddish black,
React completely under reflux conditions, after being down to room temperature, add saturation NH4The quenching reaction of Cl solution, is extracted with ethyl acetate, merges
Organic phase, decompression boils off solvent, and column chromatography for separation obtains red solid 2,3- bis- (3- indoles)-N- methylmaleimido；
(4) synthesis of 6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Add 2,3- bis- (3- indoles)-N- methylmaleimido in reaction vessel, and add butanone so that it is dissolved, then
Add potassium carbonate and copper chloride, reaction unit is reacted in 85 DEG C of oil bath pans, in course of reaction, TLC tracking and monitoring is anti-to raw material
Completely room temperature, suction filtration, extraction should be cooled to, clean organic phase, Ran Houshui with the hydrochloric acid solution that molar concentration is 0.1mol/L
Wash, anhydrous magnesium sulfate is dried, decompression boils off solvent, obtains light yellow solid 6- Methvl-indole [2,3-a] pyrroles [3,4-c] click
Azoles -5,7- diketone；
(5) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride
6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and mass concentration is added in reaction vessel
Potassium hydroxide solution for 10%, under magnetic agitation in 90 DEG C of oil baths back flow reaction, course of reaction TLC tracking and monitoring is to raw material
Completely, after being down to room temperature, the hydrochloric acid solution with molar concentration as 2mol/L is quenched reaction for reaction, occurs yellow in a large number in reaction vessel
Color solid, after being in neutrality to solution, room temperature is uniformly mixed, suction filtration, and washing obtains Tan solid indoles [2,3-a] pyrroles
[3,4-c] carbazole -5,6- dicarboxylic anhydride；
(6) synthesis of 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Add indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride and oxolane in reaction vessel, then drip
Plus hydrazine hydrate, heat in 45 DEG C of oil bath, react under counterflow condition, completely, decompression boils off TLC tracking and monitoring to raw material reaction
Solvent, add water appearance a large amount of yellow mercury oxides, suction filtration, petroleum ether is washed, obtain yellow solid 6- amino-indole [2,3-a] pyrroles [3,
4-c] carbazole -5,7- diketone.
Anticancer pharmaceutical composition of the present invention is it is characterised in that include indoles [2, the 3-a] pyrrole with active anticancer
Cough up [3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound or and its pharmaceutically acceptable salt and pharmaceutically may be used
The carrier accepting.
The preparation method raw material of the present invention is cheap and easy to get, simple to operate, indoles [2,3-a] pyrroles [3, the 4-c] click of preparation
Azoles -5,7- diketone -6 (thiosemicarbazone) compound has preferable biologically active, has in preparing anti-cancer drug compounds
Preferably application prospect.
Specific embodiment
By the following examples the above of the present invention is described in further details, but this should not be interpreted as this
The scope inventing above-mentioned theme is only limitted to below example, all belongs to this based on the technology that the above of the present invention is realized
Bright scope.
Embodiment
(1) synthesis of 2,3- dichloro maleic anhydride
Reaction scheme：
Reactions steps：
Add 9.8g (0.1mol) maleic anhydride in the 250mL round-bottomed flask being dried, under condition of ice bath, add thionyl chloride
100mL (1.38mol), magnetic agitation uniformly, drips pyridine 16.6mL (0.2mol), 1h completion of dropping with constant pressure funnel.
After completion of dropping, under condition of ice bath, continue stirring 1h.Remove ice bath, oil bath heating to 75 DEG C, flow back 40min.Decompression boils off residual
The thionyl chloride staying, obtains yellow, waxy solid.Leached with toluene, suction filtration, obtained yellow filtrate, be repeated several times general to solid
Till white.Merging filtrate, decompression obtains crude product 10.9g, yield 65.9% after boiling off solvent.
(2) synthesis of 2,3- Dichloro-N-methyl maleimide
Reaction scheme：
Reactions steps：
2,3- dichloro maleic anhydride 10.9g (65.9mmol) and methylamine hydrochloride 4.42g is added in 250mL round-bottomed flask
(65.9mmol) glacial acetic acid 100mL, magnetic agitation 6h under counterflow condition, are added, TLC tracing detection to reaction is completely.Solution is in
Crineous, after being down to room temperature, add water 100mL, with ethyl acetate extraction, uses saturated sodium bicarbonate solution and saturated aqueous common salt successively
Cleaning, decompression boils off solvent, obtains brown crude product, column chromatography for separation (volume ratio petroleum ether：Ethyl acetate=9:1, silica gel 200-
300 mesh) obtain white flaky solid 7.3g, yield 62%.
(3) synthesis of 2,3- bis- (3- indoles)-N- methylmaleimido
Reaction scheme：
Reactions steps：
The preparation of a bromoethane RMgBr
N2Under protection, in 250mL three-necked bottle, add magnesium rod 1.5g (61.6mmol), add absolute ether 10mL, dropping
Bromoethane 4.56mL (61.6mmol), after low-grade fever makes initiation, is stirred vigorously, is slowly added dropwise bromoethane, makes solvent keep micro-boiling shape
State.Completion of dropping, adds absolute ether 10mL, reacts fully in 40 DEG C of backflow about 1h, obtains the examination of smoky gray bromoethane grignard
Agent.
The preparation of b indoles RMgBr and the preparation of 2,3- bis- (3- indoles)-N- methylmaleimido
First in reaction bulb, add THF (10mL), add 40mL indoles and 7.2g (61.6mmol) bromoethane RMgBr
Toluene solution, solution turns black, and reacts about 1h in 40 DEG C.Add 40mL2,3- Dichloro-N-methyl maleimide 5g
(28mmol) toluene solution, about 40min completion of dropping, solution is in reddish black.About 6h reaction is reacted completely under counterflow condition.Fall
To room temperature, add 80mL saturation NH4The quenching reaction of Cl solution, is extracted with ethyl acetate (5 × 50mL), merges organic phase, subtract
Pressure boils off solvent, column chromatography for separation (volume ratio petroleum ether：Ethyl acetate=3:1, silica gel 200-300 mesh) obtain red solid
5.26g, yield 55.1%.
(4) synthesis of 6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Reaction scheme：
Add 2,3- bis- (3- indoles)-N- methylmaleimido 2.0g (5.87mmol) in 250mL round-bottomed flask, and
Plus 200mL butanone makes it dissolve, add potassium carbonate 4.0g (29mmol) and copper chloride 1.58g (11.73mmol), by reaction dress
It is placed in reaction, TLC tracking and monitoring in course of reaction in 85 DEG C of oil bath pans, 2h fundamental reaction is complete.It is cooled to room temperature, suction filtration, extraction
Take, clean organic phase with the hydrochloric acid solution that molar concentration is 0.1mol/L, then wash, anhydrous magnesium sulfate is dried, vacuum distillation
Boil off solvent, obtain light yellow solid 1.59g, yield 80%.
(5) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride
Reaction scheme：
6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone 238mg is added in 25mL round-bottomed bottle
(0.70mmol), add the potassium hydroxide solution 10mL that mass concentration is 10%, return in 90 DEG C of oil bath pan under magnetic agitation
Stream reaction about 3h, TLC tracking and monitoring is complete to raw material reaction.Hydrochloric acid solution after being down to room temperature, with molar concentration as 2mol/L
, a large amount of yellow solids in quenching reaction in flask, 1h, suction filtration are stirred at room temperature, then wash, obtain Huang after being in neutrality to solution
Brown solid 205mg (90%).
(6) synthesis of 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone.
Reaction scheme：
Reactions steps：
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride 56mg is added in 50mL round-bottomed flask
(0.17mmol) with THF (10mL), drip hydrazine hydrate, solution becomes clarification by muddy, heating, counterflow condition in 45 DEG C of oil bath
Lower reaction.To raw material reaction completely, decompression boils off solvent to TLC tracking and monitoring, adds about 30mL water, a large amount of yellow mercury oxides,
Suction filtration, petroleum ether is washed, and obtains yellow solid 20mg, yield 34%.
(7) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound
Reaction scheme：
Reactions steps：
51.2mg (0.15mmol) 6- amino-indole [2,3-a] pyrroles [3,4-c] click is added in 25mL round-bottomed flask
Azoles -5,7- diketone and ionic liquid BMIM BF45mL, is subsequently adding the PITC of different replacements
(0.15mmol), react under 85 DEG C of counterflow conditions, TLC tracking and monitoring is complete to raw material reaction.After reaction terminates, it is cooled to room
Temperature, mixes sample, column chromatography for separation (dichloromethane：Methyl alcohol=50:1) obtain yellow solid.Raw material is different, and corresponding product sees below
Table：
The synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- thiosemicarbazones
Product data characterizes：
1-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-6(7H,12H,13H)-
yl)-3-phenylthiourea(3a)
1H NMR(400MHz,DMSO-d6) δ 11.88 (s, 2H), 10.37 (s, 1H), 10.09 (s, 1H), 9.00 (d, J=
8.0Hz, 2H), 7.87 (d, J=8.0Hz, 2H), 7.62 7.58 (m, 2H), 7.40 (ddd, J=24.0,16.0,8.0Hz,
6H), 7.19 (d, J=8.0Hz, 1H).
1-(2-chlorophenyl)-3-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]
carbazol-6(7H,12H,13H)-yl)thiourea(3b)
1H NMR(400MHz,DMSO-d6) δ 12.51 (s, 2H), 10.33 (s, 1H), 10.22 (s, 1H), 9.00 (d, J=
8.0Hz, 2H), 7.95 (s, 1H), 7.79 (d, J=8.0Hz, 2H), 7.59 (t, J=6.0Hz, 2H), 7.49 (d, J=8.0Hz,
1H),7.43–7.34(m,3H),7.34–7.26(m,1H).
1-(3-chlorophenyl)-3-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]
carbazol-6(7H,12H,13H)-yl)thiourea(3c)
1H NMR(400MHz,DMSO-d6) δ 11.90 (s, 2H), 10.44 (s, 1H), 10.26 (s, 1H), 8.99 (d, J=
8.0Hz, 2H), 7.86 (t, J=10.0Hz, 3H), 7.64 7.57 (m, 3H), 7.43 7.38 (m, 3H), 7.24 (d, J=
8.0Hz,1H).
1-(4-chlorophenyl)-3-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]
carbazol-6(7H,12H,13H)-yl)thiourea(3d)
1H NMR(400MHz,DMSO-d6) δ 11.91 (s, 2H), 10.42 (s, 1H), 10.21 (s, 1H), 9.00 (d, J=
8.0Hz, 2H), 7.93 7.81 (m, 3H), 7.61 (t, J=8.0Hz, 2H), 7.51 (d, J=8.0Hz, 1H), 7.41 (t, J=
8.0Hz,4H).
1-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-6(7H,12H,13H)-
yl)-3-(2-fluorophenyl)thiourea(3e)
1H NMR(400MHz,DMSO-d6) δ 11.89 (s, 2H), 10.28 (s, 1H), 10.25 (s, 1H), 9.01 (d, J=
8.0Hz, 2H), 7.87 (d, J=8.0Hz, 2H), 7.61 (t, J=6.0Hz, 2H), 7.45 7.21 (m, 6H).
1-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-6(7H,12H,13H)-
yl)-3-(4-fluorophenyl)thiourea(3f)
1H NMR(400MHz,DMSO-d6) δ 11.98 (s, 2H), 10.38 (s, 1H), 10.14 (s, 1H), 8.99 (d, J=
8.0Hz, 2H), 7.85 (d, J=8.0Hz, 2H), 7.60 (t, J=8.0Hz, 3H), 7.39 (dd, J=12.0,8.0Hz, 3H),
7.28–7.09(m,2H).
1-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-6(7H,12H,13H)-
yl)-3-(3-methoxyphenyl)thiourea(3g)
1H NMR(400MHz,DMSO-d6) δ 12.82 (s, 2H), 10.34 (s, 1H), 10.07 (s, 1H), 8.99 (d, J=
8.0Hz, 2H), 7.80 (d, J=8.0Hz, 2H), 7.58 (t, J=8.0Hz, 2H), 7.38 (s, 2H), 7.22 (d, J=8.0Hz,
1H), 7.14 (s, 1H), 7.05 (d, J=4.0Hz, 1H), 6.75 (d, J=8.0Hz, 1H), 3.80 3.72 (m, 3H).
1-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-6(7H,12H,13H)-
yl)-3-(3-nitrophenyl)thiourea(3h)
1H NMR(400MHz,DMSO-d6) δ 11.90 (s, 2H), 10.67 (s, 1H), 10.44 (s, 1H), 9.00 (d, J=
8.0Hz, 2H), 8.47 (s, 1H), 8.08 8.01 (m, 2H), 7.87 (d, J=8.0Hz, 2H), 7.64 7.55 (m, 3H), 7.41
(t, J=8.0Hz, 2H).
1-(4-bromophenyl)-3-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]
carbazol-6(7H,12H,13H)-yl)thiourea(3i)
1H NMR(400MHz,DMSO-d6) δ 11.95 (s, 2H), 10.40 (s, 1H), 10.19 (s, 1H), 8.99 (d, J=
8.0Hz, 2H), 7.84 (t, J=12.0Hz, 2H), 7.63 7.36 (m, 8H).
1-(5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-6(7H,12H,13H)-
yl)-3-(pyridin-3-yl)thiourea(3j)
1H NMR(400MHz,DMSO-d6) δ 11.91 (s, 2H), 10.50 (s, 1H), 10.34 (s, 1H), 9.00 (d, J=
8.0Hz, 2H), 7.94 7.82 (m, 4H), 7.60 (t, J=8.0Hz, 2H), 7.46 7.36 (m, 4H).
Compound high-resolution data
Activity research
Preliminary biological activity test shows, 3,4- bis- (3- indoles) -3- pyrrolin -2,5- diketone -1- thiosemicarbazide
There is good inhibiting effect in compound on intracellular cycle division protein 25 B (CDC 25B), and 3,4- bis- (3- indoles) -3- pyrrolin -
2,5- diketone -1- thiosemicarbazide compound see table to CDC 25B inhibiting rate.Test concentrations are all in 20 μ g/mL.
Indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6 thiosemicarbazones is to CDC25B inhibiting rate
Above example technological thought only to illustrate the invention is it is impossible to limit protection scope of the present invention with this, every
According to technological thought proposed by the present invention, any change done on the basis of technical scheme, each fall within the scope of the present invention
Within.
Claims (5)
1. there are indoles [2,3-a] pyrroles [3,4-c] carbazole -5 of active anticancer, 7- diketone -6- (thiosemicarbazone) compound,
It is characterized in that with replace isosulfocyanate compound R-NCS and 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole-
5,7- diketoneIt is prepared from for raw material, its general structure is：
Wherein R is
2. indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- with active anticancer described in a kind of claim 1
The preparation method of (thiosemicarbazone) compound is it is characterised in that concrete synthesis step is：It is initially charged 6- ammonia in reaction vessel
Base-indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and ionic liquid, are subsequently adding replacement isosulfocyanate chemical combination
Thing, reacts under 85 DEG C of counterflow conditions, and TLC follows the tracks of, and reaction is dried in the air after terminating to room temperature, and decompression boils off solvent, and column chromatography for separation obtains
To yellow solid indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound, concrete reaction side
Formula is：
Wherein replacing isosulfocyanate compound is one of structure set forth below：
3. indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- with active anticancer according to claim 2
The preparation method of (thiosemicarbazone) compound it is characterised in that：Described 6- amino-indole [2,3-a] pyrroles [3,4-c] click
Azoles -5,7- diketone is 1 with the molar ratio replacing isosulfocyanate compound:1.2.
4. indoles [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone -6- with active anticancer according to claim 2
The preparation method of (thiosemicarbazone) compound is it is characterised in that described 6- amino-indole [2,3-a] pyrroles [3,4-c] click
Azoles -5,7- diketone is prepared from by following methods：
(1) synthesis of 2,3- dichloro maleic anhydride
Add maleic anhydride in reaction vessel, under condition of ice bath, add thionyl chloride, magnetic agitation uniformly, uses constant pressure funnel
Dropping pyridine, after completion of dropping, continues stirring reaction under condition of ice bath, then removes ice bath, oil bath heating flows back, decompression boils off
Residual thionyl chloride, obtain yellow, waxy solid, then leached with toluene, suction filtration, obtain yellow filtrate, be repeated several times to
Till solid whiting, merging filtrate, decompression obtains crude product 2,3- dichloro maleic anhydride after boiling off solvent；
(2) synthesis of 2,3- Dichloro-N-methyl maleimide
Add 2,3- dichloro maleic anhydride, methylamine hydrochloride and glacial acetic acid in reaction vessel, magnetic agitation reaction under counterflow condition,
To raw material reaction completely, solution is in crineous to TLC tracking and monitoring, adds water after being down to room temperature, with ethyl acetate extraction, successively with satisfying
With sodium bicarbonate solution and saturated aqueous common salt cleaning, reduce pressure and boil off solvent, obtain brown crude product, column chromatography for separation obtains white tablets
Shape solid 2,3- Dichloro-N-methyl maleimide；
(3) synthesis of 2,3- bis- (3- indoles)-N- methylmaleimido
The preparation of a bromoethane RMgBr
N2Under protection, add magnesium rod and absolute ether in reaction vessel, and drip bromoethane, acutely stir after low-grade fever initiation reaction
Mix, dropping bromoethane makes solvent keep slight boiling condition, adds absolute ether, backflow reacts fully, and obtains cigarette after completion of dropping
Grey bromoethane RMgBr,
The preparation of b indoles RMgBr and the preparation of 2,3- bis- (3- indoles)-N- methylmaleimido
To in reaction vessel, first add the toluene solution of oxolane, indoles and bromoethane RMgBr, solution turns black, in 40
DEG C reaction, is subsequently adding the toluene solution of 2,3- Dichloro-N-methyl maleimide, completion of dropping, and solution is in reddish black, is returning
React completely under the conditions of stream, after being down to room temperature, add saturation NH4The quenching reaction of Cl solution, is extracted with ethyl acetate, merges organic
Phase, decompression boils off solvent, and column chromatography for separation obtains red solid 2,3- bis- (3- indoles)-N- methylmaleimido；
(4) synthesis of 6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Add 2,3- bis- (3- indoles)-N- methylmaleimido in reaction vessel, and add butanone so that it is dissolved, add
Potassium carbonate and copper chloride, reaction unit are reacted in 85 DEG C of oil bath pans, in course of reaction, TLC tracking and monitoring is complete to raw material reaction
Entirely, it is cooled to room temperature, suction filtration, extraction, clean organic phase with the hydrochloric acid solution that molar concentration is 0.1mol/L, then wash, no
Water magnesium sulfate is dried, and decompression boils off solvent, obtains light yellow solid 6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,
7- diketone；
(5) synthesis of indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride
To in reaction vessel, addition 6- Methvl-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone and mass concentration are
10% potassium hydroxide solution, under magnetic agitation in 90 DEG C of oil baths back flow reaction, course of reaction TLC tracking and monitoring is anti-to raw material
Should completely, after being down to room temperature, the hydrochloric acid solution with molar concentration as 2mol/L is quenched reaction, a large amount of yellow in reaction vessel
Solid, after being in neutrality to solution, room temperature is uniformly mixed, suction filtration, and washing obtains Tan solid indoles [2,3-a] pyrroles
[3,4-c] carbazole -5,6- dicarboxylic anhydride；
(6) synthesis of 6- amino-indole [2,3-a] pyrroles [3,4-c] carbazole -5,7- diketone
Add indoles [2,3-a] pyrroles [3,4-c] carbazole -5,6- dicarboxylic anhydride and oxolane in reaction vessel, then drip water
Close hydrazine, heat in 45 DEG C of oil bath, react under counterflow condition, completely, decompression boils off molten TLC tracking and monitoring to raw material reaction
Agent, add water a large amount of yellow mercury oxides of appearance, suction filtration, and petroleum ether is washed, and obtains yellow solid 6- amino-indole [2,3-a] pyrroles [3,4-
C] carbazole -5,7- diketone.
5. a kind of anticancer pharmaceutical composition is it is characterised in that include the indoles [2,3- with active anticancer described in claim 1
A] pyrroles [3,4-c] carbazole -5,7- diketone -6- (thiosemicarbazone) compound or/and its pharmaceutically acceptable salt and medicine
Acceptable carrier on.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114394971A (en) * | 2022-01-24 | 2022-04-26 | 云南大学 | Preparation method of indole carbazole compound |
| CN116041248A (en) * | 2023-04-03 | 2023-05-02 | 成都摩诃大龙医药科技有限公司 | Carbazole derivative with anticancer activity and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018766A1 (en) * | 1992-03-20 | 1993-09-30 | The Wellcome Foundation Limited | Further indole derivatives with antiviral activity |
| EP0602597A2 (en) * | 1992-12-14 | 1994-06-22 | Banyu Pharmaceutical Co., Ltd. | Process for preparation of indolopyrrolocarbazole derivatives |
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- 2016-09-07 CN CN201610808997.2A patent/CN106432250B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993018766A1 (en) * | 1992-03-20 | 1993-09-30 | The Wellcome Foundation Limited | Further indole derivatives with antiviral activity |
| EP0602597A2 (en) * | 1992-12-14 | 1994-06-22 | Banyu Pharmaceutical Co., Ltd. | Process for preparation of indolopyrrolocarbazole derivatives |
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| ELISABETE RODRIGUES PEREIRA，等: "Structure-Activity Relationships in a Series of Substituted Indolocarbazoles：Topoisomerase I and Protein Kinase C Inhibition and Antitumoral and Antimicrobial Properties", 《J. MED. CHEM.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114394971A (en) * | 2022-01-24 | 2022-04-26 | 云南大学 | Preparation method of indole carbazole compound |
| CN114394971B (en) * | 2022-01-24 | 2023-01-31 | 云南大学 | Preparation method of indole carbazole compound |
| CN116041248A (en) * | 2023-04-03 | 2023-05-02 | 成都摩诃大龙医药科技有限公司 | Carbazole derivative with anticancer activity and preparation method and application thereof |
| CN116041248B (en) * | 2023-04-03 | 2023-06-06 | 成都摩诃大龙医药科技有限公司 | Carbazole derivative with anticancer activity and preparation method and application thereof |
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