CN108752360B - A kind of compound and preparation method thereof for treating baby diarrhea - Google Patents

A kind of compound and preparation method thereof for treating baby diarrhea Download PDF

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Publication number
CN108752360B
CN108752360B CN201810326026.3A CN201810326026A CN108752360B CN 108752360 B CN108752360 B CN 108752360B CN 201810326026 A CN201810326026 A CN 201810326026A CN 108752360 B CN108752360 B CN 108752360B
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compound
formula
carbonyl
alkyl
hydrogen
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CN108752360A (en
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董丽滨
张娟
张宇
林士珊
高春梅
王彤彤
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Mudanjiang Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Abstract

The present invention relates to a kind of compound of formula I or its pharmaceutically acceptable salts.The compound has good inhibiting effect for rotavirus, therapeutic index is more than 39, compared with virazole, the compounds of this invention has close cytotoxicity, but with considerably better anti-rotavirus activity, therefore it can be used for effectively treating baby diarrhea for the therapeutic effect of rotavirus far more than virazole.

Description

A kind of compound and preparation method thereof for treating baby diarrhea
Technical field
The present invention relates to field of medicaments, in particular it relates to a kind of compound for treating baby diarrhea and its Preparation method.
Background technique
Baby diarrhea, one group of disease caused by being more cause of diseases, being multifactor based on diarrhea.It is mainly characterized in that times of defecation Increase and changes with character, it can be with the symptoms such as fever, vomiting, abdominal pain and different degrees of water, electrolyte, disturbance of acid-base balance.Disease Original can be by virus (predominantly rotavirus and poliovirus, Coxsackie virus, EHCO virus and new enterovirus Deng), bacterium (enteropathogenic E. Coli, enterotoxigenic E. Coli, Enterohemorrhagic E.coli, enteroinvasive E. Coli and mouse wound Cold salmonella, campylobacter jejuni, yersinia enterocolitica, S. aureus L-forms etc.), helminth, fungi etc. cause, be the normal of 2 years old Infants Below See disease.Light-duty diarrhea has gastrointestinal symptom, and constitutional symptom is unobvious, and body temperature is normal or has low-heat, and no water electrolyte and soda acid are flat Weighing apparatus disorder；Heavy diarrhea is in addition to having serious gastrointestinal symptom, also with the Water-Electrolyte of severe and disturbance of acid-base balance, obvious Systemic toxicity profiles symptom (fever, it is irritated, apathetic, drowsiness in addition stupor, suffer a shock).
Therefore, those skilled in the art is dedicated to developing a kind of compound that can effectively treat baby diarrhea.
Summary of the invention
To achieve the above object, the present invention provides one kind to have the active compound of anti-rotavirus and its preparation side Method, application, the compound can be used for treating baby diarrhea.
From on one side, the present invention provides one kind have the active compound of formula I of anti-rotavirus or its pharmaceutically Acceptable salt:
Wherein:
R1、R2、R3It is identical or different, be each independently selected from hydrogen, hydroxyl, amino, C1-C6 alkyl, C1-6 alkoxy or C1-6 alkyl amino；
R4、R5It is identical or different, it is each independently selected from hydrogen, hydroxyl or C1-C6 alkyl or R4、R5It is formed together carbonyl Base；
Hy indicate heteroaryl, optionally by it is one or more selected from halogen, hydroxyl, amino, cyano, C1-C6 alkyl, The group of C1-6 alkoxy or C1-6 alkyl amino replaces；
R6Indicate hydrogen, C1-C6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy carbonyl or C1-6 alkyl amino-carbonyl.
In a preferred embodiment of the present invention, the R1、R2、R3It is hydrogen.
In a preferred embodiment of the present invention, the R4、R5Selected from hydrogen or hydroxyl or R4、R5It is formed together carbonyl Base.
In a preferred embodiment of the present invention, the heteroaryl basis representation has the 1-4 miscellaneous originals for being selected from N, O and S Son five or hexa-atomic aromatic ring yl or their benzene condense ring group, it is preferable that the heteroaryl basis representation pyridyl group, pyrimidine radicals, Thienyl or isoquinolyl.
In a preferred embodiment of the present invention, the R6Selected from hydrogen, methyl, methyl carbonyl, ethoxy carbonyl or Amino-carbonyl.
In a preferred embodiment of the present invention, the compound is selected from:
In the present invention, term halogen refers to fluorine, chlorine, bromine or iodine.
In the present invention, term C1-C6 alkyl refers to the alkyl of the linear chain or branched chain with 1-6 carbon atom, such as methyl, second Base, propyl, isopropyl and butyl.Preferred alkyl is methyl.
In the present invention, term heteroaryl basis representation has 1-4 heteroatomic five or the hexa-atomic aromatic ring yls for being selected from N, O and S Or their benzene condenses ring group, when the ring member nitrogen atoms are N or S.Heteroaryl is, for example, pyrrole radicals, indyl, furans Base, benzofuranyl, thienyl, benzothienyl, thiazolyl, benzothiazolyl, imidazole radicals, benzimidazolyl, triazole, four Azoles, pyridyl group, pyrazolyl, pyrimidine radicals, pyrazinyl, triazine radical, quinolyl or isoquinolyl.Preferred heteroaryl be pyridyl group, Pyrimidine radicals, thienyl and isoquinolyl.
For substituent group, term " independently " refers to that substituent group can be same or different to each other in identical molecule.
The compound of the present invention can contain one or more asymmetric centers, and therefore can be mixed with racemic modification and racemic Object, single enantiomter, the mixture of diastereomer and individual diastereoisomer exist.Other asymmetric centers can be with In the presence of property depending on substituent groups various on molecule.Each such asymmetric center generates two optical isomerisms for independent Body, it means that as a mixture with all possible optical isomer of purifying or partially purified compound form and Diastereoisomer is included within the scope of the invention.The present invention mean include these compounds all such isomeries Form.These diastereoisomers be separately synthesized or their chromatographic isolation can pass through according to methods known in the art it is appropriate The methods disclosed herein is improved to complete in ground.If it is desired, the racemic mixture of separable compound is single to separate Enantiomer.It can be separated by methods known in the art, such as the racemic mixture and enantiomer-pure by compound Compound is coupled the mixture to form diastereomer, later by standard method such as fractional crystallization or single non-right of chromatographic isolation Reflect body.
Compound can exist with polymorphic form, be identically included in the scope of the present invention.In addition, compound can Solvate is formed with water (i.e. hydrate) or the organic solvent of routine, such solvate is also included within the scope of the present invention It is interior.
Term " pharmaceutically acceptable salt " refers to those salt: within a reasonable range of medical judgment, suitable for people and The tissue of lower animal contacts without improperly toxicity, stimulation, allergy etc., has reasonable benefit/hazard ratio.Pharmacy Upper acceptable salt is known in this field.They can be prepared in situ when separating and purifying the compounds of this invention, or by making it With pharmaceutically acceptable nontoxic alkali or acid, including inorganic or organic base and inorganic or organic acid reaction it is independently prepared.Example The salt of property includes sulfate, acetate, oxalates, chloride, bromide, iodide, nitrate, isonicotinic acid salt, lactate, water Poplar hydrochlorate, succinate, maleate, fumarate, formates and mesylate etc..
Another aspect provides a kind of pharmaceutical compositions, include at least one the compound of the present invention and its medicine Acceptable salt and any ingredient, carrier, diluent or excipient for being pharmaceutically suitable on.
" pharmaceutically suitable " refers to that carrier, diluent or excipient must be compatible with other ingredients in preparation and connect it Receptor is harmless.
Typical composition is prepared by mixing the compounds of this invention and carrier, diluent or excipient.
Suitable carrier, diluent or excipient can enumerate such as: syrup, Arabic gum, gelatin, sorbierite, tragacanth, Cellulose and its derivates, gelatine size, syrup, starch slurry or polyvinylpyrrolidone, lactose, Icing Sugar, dextrin, starch and its spread out Biology, cellulose and its derivates, inorganic calcium salt, sorbierite or glycine, calcium sulfate, calcium phosphate, calcium monohydrogen phosphate or sedimentation carbon Sour calcium etc., superfine silica gel powder, magnesium stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil or polyethylene glycol, starch, poly- second Alkene pyrrolidone or microcrystalline cellulose, lauryl sodium sulfate, water or alcohol etc..
The composition can also include surfactant, wetting agent, glidant, buffer, solubilizer, preservative, Lubricant, emulsifier, flavoring agent, antioxidant, colorant, opacifier, sweetener, aromatic and other known additive.
The exact dose and dosage regimen of the compounds of this invention and combinations thereof will be living dependent on the biology of compound itself Property, the age of patient, weight and gender, the needs of individual for receiving medicament administration, the degree of pain or needs and operation doctor The judgement of teacher.In general, parenteral administration requirement is lower than reling more on the dosage of other medications of absorption.However, for people For dosage be preferably 0.001-10mg/kg weight.In general, the dosage through enteron aisle and parenteral administration will daily 0.1 to In the range of the Active principals of 1000mg.
The compound of the present invention can be used alone, or be used in combination with other therapeutic agents.Combination therapy can provide Synergistic effect, i.e., the effect reached when active constituent is used together, greater than respectively using effect produced by the compound Adduction.
Another aspect provides the compound of formula I or its pharmaceutically acceptable salts in medicine preparation Purposes, the drug be used for anti-rotavirus.
Another aspect provides the compound of formula I or its pharmaceutically acceptable salts in medicine preparation Purposes, the drug is for treating baby diarrhea.
Another aspect provides the method for preparing compound of formula I, the described method comprises the following steps:
Step 1: Formula II compound is reacted into production IV compound with formula III compound
Step 2: formula IV compound is reacted with Formula V compound and generates compound of formula I
Wherein, R1-R6Definition it is as described herein, X1、X2Each independently represent halogen, preferably chlorine, bromine or iodine.
Beneficial effect
The compounds of this invention has good inhibiting effect for rotavirus, and therapeutic index is more than 39, with virazole phase There is close cytotoxicity than, the compounds of this invention, but with considerably better anti-rotavirus activity, therefore it is for wheel The therapeutic effect of shape virus can be used for effectively treating baby diarrhea far more than virazole.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
Those skilled in the art will realize that: chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds mostly of the invention, and other methods for the preparation of the compounds of the present invention are considered as in model of the invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention It is completed by method of modifying, such as protection interference group appropriate, by utilizing other known reagent in addition to described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
Embodiment 1:(E) -1'- (1- methyl piperidine -4- base) -5- (2- (pyridin-3-yl) vinyl) spiral shell [benzo dihydro pyrrole Mutter -2,4'- piperidines] (compound 1)
Step 1: 5- iodine spiral shell [benzodihydropyran -2,4'- piperidines] hydrochloride 10.0mmol is taken, the ethyl alcohol of 150ml is dissolved in In, the cesium carbonate aqueous solution 20ml of 2N is added, the bromo- 1- methyl piperidine of 4- that 10.0mmol is then added is dissolved in 50ml ethyl alcohol Solution is stirred to react at reflux, and TCL monitors reaction process, and reaction terminates after 5 hours；Solvent evaporated is concentrated under reduced pressure, uses Water is diluted and is extracted with chloroform, is concentrated to get residue after depressurizing after organic layer is dry, is made with ethyl acetate/petroleum ether (1/20) Silica gel column chromatography, the isolated iodo- 1'- of 5- (1- methyl piperidine -4- base) spiral shell [benzodihydropyran -2,4'- are carried out for mobile phase Piperidines] 3.77g, yield 88.4%.Mass spectrum (ESI): 427 [M+H]+
Step 2: by the iodo- 1'- of 5- (1- methyl piperidine -4- base) spiral shell [benzodihydropyran -2,4'- piperazine under nitrogen protection Pyridine] 5.0mmol and-three potassium fluoborate 6.0mmol of 2- (pyridin-3-yl) vinyl be added in 100ml toluene, add 15ml Then water sequentially adds cesium carbonate 20.0mmol and tetrakis triphenylphosphine palladium 0.1mmol.The lower reaction of reflux overnight, reacts liquid cooling But to after room temperature with ethyl acetate dilution, filter and be washed with brine.It is concentrated to get residue after depressurizing after organic layer is dry, is used Methanol/petroleum ether (1/10) carries out silica gel column chromatography, isolated target compound 1.23g, yield 61.2% as mobile phase.
Mass spectrum (ESI): 404 [M+H]+
Hydrogen composes (400MHz, DMSO) δ 8.92 (s, 1H), 8.33 (d, 1H), 8.11 (d, 1H), 7.65 (t, 1H), 7.44 (t, 1H),7.24(d,1H),6.83-6.88(m,2H),6.70(d,1H),2.87(t,2H),2.72(t,2H),2.63(m,1H), 2.54-2.58(m,8H),2.25(s,3H),1.90-1.95(m,8H)。
Embodiment 2:(E) -5- (2- (isoquinolin -4- base) vinyl) -1'- (1- methyl piperidine -4- base) spiral shell [benzo dihydro Pyrans -2,4'- piperidines] -4- ketone (compound 2)
Step 1: 5- iodine spiral shell [benzodihydropyran -2,4'- piperidines] -4- keto hydrochloride 10.0mmol is taken, 150ml is dissolved in Ethyl alcohol in, the cesium carbonate aqueous solution 20ml of 2N is added, then be added 10.0mmol the bromo- 1- methyl piperidine of 4- be dissolved in 50ml second Solution in alcohol, is stirred to react at reflux, and TCL monitors reaction process, and reaction terminates after 8 hours；Reduced pressure is evaporated Solvent is diluted with water and is extracted with chloroform, residue is concentrated to get after depressurizing after organic layer is dry, with ethyl acetate/hexamethylene (1/30) silica gel column chromatography, the isolated iodo- 1'- of 5- (1- methyl piperidine -4- base) spiral shell [benzo dihydro pyrrole are carried out as mobile phase Mutter -2,4'- piperidines] -4- ketone 3.74g, yield 85.1%.Mass spectrum (ESI): 441 [M+H]+
Step 2: by the iodo- 1'- of 5- (1- methyl piperidine -4- base) spiral shell [benzodihydropyran -2,4'- piperazine under nitrogen protection Pyridine] -4- ketone 5.0mmol and 2- (isoquinolin -4- base) vinyl-three potassium fluoborate 6.0mmol be added 100ml toluene in, then plus Enter 15ml water, then sequentially adds cesium carbonate 20.0mmol and tetrakis triphenylphosphine palladium 0.1mmol.The lower reaction of reflux is stayed overnight, instead It diluted, filter and is washed with brine with ethyl acetate after answering liquid to be cooled to room temperature.It is concentrated to get after being depressurized after organic layer is dry residual Excess uses methanol/petroleum ether (1/8) to carry out silica gel column chromatography, isolated target compound 1.26g, yield as mobile phase 54.3%.
Mass spectrum (ESI): 468 [M+H]+
Hydrogen composes (400MHz, DMSO) δ 8.82 (s, 1H), 8.63 (s, 1H), 7.43-7.93 (m, 5H), 7.25 (d, 1H), 7.03(d,1H),6.88(d,1H),6.73(d,1H),2.75(s,2H),2.64(m,1H),2.53-2.58(m,8H),2.25 (s,3H),1.92-1.98(m,8H)。
In a similar way, corresponding raw material is used to synthesize following embodiment compound:
Effect example: anti-rotavirus activity test
Anti-rotavirus uses cell in vitro method of testing to pass through after that is, sample and virus act on MA104 cell simultaneously Alarmablue method test sample causes the protective effect of cell death to virus infection, to measure work of the sample to rotavirus Property effect.
1, the cytotoxicity detection of drug
MA104 cell is cultivated in 96 porocyte culture plates form single layer after, the sample liquid of various concentration is added, continues to train After supporting 3 days, the culture solution containing Alamarblue is replaced, the fluorescent value at its 530/590nm is detected after continuing culture 2~3 hours, To which test sample is to the toxicity of MA104 cell, and calculate half cytotoxic concentration (TC50)。
2, drug anti-rotavirus effect detection
MA104 cell is cultivated in 96 porocyte culture plates form single layer after, the virus liquid of 100TCID50 and be no more than The gradient concentration drug solution of 20% cytotoxicity is added on MA104 cell simultaneously, and after continuing culture 4-6 days, replacement contains The culture solution of Alamarblue detects the fluorescent value at its 530/590nm after continuing culture 2~3 hours, and calculates half inhibition Concentration (IC50)。
3, the therapeutic index of compound is calculated
According to TC50/IC50The therapeutic index for calculating compound, is as a result shown in following table 1:
Table 1: anti-rotavirus activity test
The result shows that the compounds of this invention has good inhibiting effect for rotavirus, therapeutic index is more than 39, with Virazole is compared, and the compounds of this invention has close cytotoxicity, but with considerably better anti-rotavirus activity, therefore Its for rotavirus therapeutic effect far more than virazole, can be used for effectively treating baby diarrhea.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple Embodiment disclosed herein can carry out the improvements and changes without departing from scope and spirit.

Claims (10)

1. one kind has the active compound of formula I of anti-rotavirus or its pharmaceutically acceptable salt:
Wherein:
R1、R2、R3It is identical or different, it is each independently selected from hydrogen, C1-C6 alkyl or C1-6 alkoxy；
R4、R5It is identical or different, it is each independently selected from hydrogen, hydroxyl or C1-C6 alkyl or R4、R5It is formed together carbonyl；
Hy indicates heteroaryl, optionally by one or more bases selected from halogen, cyano, C1-C6 alkyl or C1-6 alkoxy Group replaces, the heteroaryl basis representation pyridyl group, pyrimidine radicals, thienyl or isoquinolyl；
R6Indicate hydrogen, C1-C6 alkyl, C1-6 alkyl-carbonyl, C1-6 alkoxy carbonyl or C1-6 alkyl amino-carbonyl.
2. compound according to claim 1, which is characterized in that the R1、R2、R3It is hydrogen.
3. compound according to claim 1, which is characterized in that the R4、R5Selected from hydrogen or hydroxyl or R4、R5Together Form carbonyl.
4. compound according to claim 1, which is characterized in that the R6Selected from hydrogen, methyl, methyl carbonyl, ethyoxyl carbonyl Base or amino-carbonyl.
5. compound according to claim 1, which is characterized in that the compound is selected from:
6. a kind of pharmaceutical composition, includes at least one compound of formula I according to claim 1 or its is pharmaceutically acceptable Salt and any pharmaceutically suitable ingredient, carrier, diluent or excipient.
7. the purposes of compound of formula I according to claim 1 or its pharmaceutically acceptable salt in medicine preparation, described Drug is used for anti-rotavirus.
8. the purposes of compound of formula I according to claim 1 or its pharmaceutically acceptable salt in medicine preparation, described Drug is for treating baby diarrhea.
9. a kind of method for preparing compound of formula I according to claim 1 comprising following steps:
Step 1: Formula II compound is reacted into production IV compound with formula III compound
Step 2: formula IV compound is reacted with Formula V compound and generates compound of formula I
Wherein, R1-R6, the definition of Hy it is as described in claim 1, X1、X2Each independently represent halogen.
10. according to the method described in claim 9, it is characterized in that, the X1、X2Each independently represent chlorine, bromine or iodine.
CN201810326026.3A 2018-04-12 2018-04-12 A kind of compound and preparation method thereof for treating baby diarrhea Active CN108752360B (en)

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CA2648831A1 (en) * 2006-05-05 2007-11-15 Ulrich Reiser Spiro- (tho) benzopyran-2, 4' -piperidine-and cyclohexane derivatives as inhibitors of specific cell cycle enzymes
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