LATVIAN INSTITUTE OF ORGANIC SYNTHESIS
DAINA JANSONE
ARYL(HETARYL) - AND -LACTONES:
SYNTHESIS AND BIOLOGICAL ACTIVITY
Abstract of the dissertation
Riga, 2004
Introduction
Lactones are of interest as biologically active compounds. In particular, it is known that
some of the synthetic and natural compounds containing unsaturated five-membered lactones
exhibit a cardiotonic activity. For example, the heart glycosides contain a -lactone unit. Beside
this, the majority of cardiotonic substances of a novel generation is derived from N-heterocyc!ic
compounds. High antitumor activity have been established for 2(3H)-furanones. Some lactones
possess bactericidal properties, and also plant stimulatory activity.
Derivatives of lactones have been synthesized using aryl (hetaryl) aldehydes condensation
with such CH-acid as - and -lactones in the presence of an alkaline catalyst. It is very well
known and widely used reaction but only during the recent years there appeared a number of
articles dedicated to the new type of aldehyde condensation reactions with CH-acid. It has been
reported in the literature that the condensation of 2- and 4-pyridinecarboxaldehydes and 2quinolinecarboxaldehyde with acetophenone and also of 2-quinolinecarboxa!dehyde with
acetaidehyde in the presence of an alkaline catalyst takes place by an untraditional mechanism,
and compounds of the Michael adduct type are formed together with the product of crotonic
condensation. The authors proposed that the Michael-type products may be formed stepwise via
crolonic condensation, followed by the addition of the second molecule of nudeophilic reagent to
the double bond. The literature data on such tandem reaction mechanism are very poor.
The aim of the work
> Synthesis of the new derivatives of unsaturated - and -lactones;
> Investigation of the reaction mechanism aimed at the mechanistic understanding of the
base-catalyzed tandem Michael-aldol reaction;
> Determination of pharmacophores responsible for cardiovascular and antitumor
activity;
> Study of biological activity of new compounds.
Results of the work
1. Synthesis of hetarylderivatives of  - and  -lactones
Reaction of the hetarylcarbaldehydes (1-7) with 4,5,5-trimethyl-2(5H)-furanone (8, 9) and
4,6,6-trimethyl-3-cyano-5,6-dihydro-2(2H)-pyranone (10) in the presence of catalytic quantity of
NaOH has been studied (Scheme 1).
Scheme 1. Synthesis of hetaryl derivatives of -lactones
A simitar reaction proceeds during the interaction of hetarylaldehydes with pyranone 10
(Scheme 2):
Scheme 2. Synthesis of hetaryl derivatives of y- and 5-lactones
We established that in the case of aldehydes 2-4, these reactions proceeded as aldol-type
reactions (products 12-14 and 25-27) in a tandem with the Michael-type reaction (products 21-23
un 29-31) regardless of lactone : aldehyde ratio. In the presence of catalytic amounts of sodium
hydroxide in ethanol solution at 20-78°C the yield of the Michael product amounted to 25-80%.
To avoid this addition we used a two-fold excess of pyridine aldehyde (Table 1 and 2).
Table 1. Synthesis of furanone 8 and 9 derivatives
The data of the Table 1 show that the reactivity of aldehyde 5 is significantly lower than
that one of aldehyde 4 (yields of furanones 16 and 14 are 21 and 69.8%, respectively). The
reaction of aldehydes 1, 5-7 with lactone 8 as well as of aldehydes 2 ,6, 7 with lactone 9 occurstraditionally and gives the corresponding unsaturated derivatives of lactones only. The isolation of
the compounds 21 and 22 from reaction mixture was a failure but the 'H NMR spectra show that
these compounds are present in reaction mixture.
The influence of reaction conditions was studied for the reaction of aldehyde 3 with
furanone 8 (Table 3). The yields of the reaction products were determined by HPLC and 'H NMR
in DMSO-d6, with TMS as internal standard without separation from reaction mixture.
At room temperature the yield of the crolonic condensation product is higher than the yield of
the Michael product. If the temperature is increased to 78°C only crotonic condensation product is
formed. On the other hand, only this product is found in the reaction mixture if the concentration of
the catalyst in the reaction mixture is increased to an aldehyde : NaOH molar ratio of 1 : 0.3.
since (as expected) the rate of the transformation along with this path is increased considerably. At
the same lime, second reaction path becomes more favorable in the absence of the catalyst, and the
main product is Michael-type product.
Table 2. Synthesis of pyranone 10 derivatives
Table 3. The effect of temperature and the amount of catalyst on the direction of
condensation reaction 1
1
Molar ratio aldehyde 3 and furanone 8 of 1:1.
Formation of those compounds is observed for any ratio of reagents, including a
significant excess of the eleclrophilic reagent compared with lactones. The optimal ratio
for the best yield is 1:2. In the 'H NMR spectra of those compounds there are no signals
from olefin protons, but we see characteristic signals from the methylene groups in the
2.9-3.5 ppm region and multiplels from methine protons coupled with protons of the two
CH2 groups at 3.5-3.9 ppm. Because of the
instability under electron impact, we took the spectra under fast atom bombardment (FAB)
conditions, and in all cases we established the presence of quasimolecular MH+ ions with m/z
420.
Under electron-impact mass spectroscopy conditions, the molecular ions of the Michael
adduct type compounds are not observed. Probably compounds decompose as follows under
electron impact and heating (Scheme 3):
Scheme 3. Decomposition of compounds 21-23, 29-31
Upon condensation conditions, compounds 21, 23 could not be isolated due to their
instability and their facile conversion to the corresponding unsaturated compounds 12, 13. The
presence of these compounds in a reaction mixture was established by TLC, 1H NMR, and mass
spectroscopy. Thus in the 1H NMR spectra of a mixture of condensation products of aldehydes
2-4 with lactone 8, along with signals from olefin protons we detected signals from methine and
rnethylene protons of the CH-CFI2 fragment, while in the mass spectra under fast atom
bombardment conditions we recorded ions with m/z 392 [MH+] and 391 [M+].
The condensation reaction is accelerated in the presence of basic catalyst. Probably the
reaction rate is determined by attack of the anion formed upon deprotonation of the methyl groups
of lactone.
In all cases the values of coupling constants of the double bond CH=CH protons in chain
CH=CH-CH=CH (16-17 Hz) indicated that only E- or E,E-isomers were isolated. Similar value
of constants (10.4 Hz) are given for C-isomer of butadiene. To obtain an additional proof for the
configuration of the unsaturated synthesized compounds, E-Z photoisomerization caused by UV
irradiation of the condensation products 12, 26, 28 and 42 was studied. The isomerization process
was controlled by electron-absorption spectroscopy. When the solution in ethanol was irradiated
with UV light the intensity of the £-isomer absorption band at 332-344 nm decreased and a band
at 220-285 nm appeared. According to 'H NMR data the formation of the E- and Z-isomer
mixture caused such changes in spectra. The spin-spin coupling constants of the double bond
CH=CH protons in isomers appeared during irradiation and were 11-13 Hz. This means that the
compounds described really have E-configuration.
In the present work we undertook a model quantum-chemical investigation of the reaction
mechanism for the case of the reaction of aldehyde 3 with furanone 8, leading to the product of
crotonic condensation 13 and the product of Michael-type addition 22 (Scheme 4):
Scheme 4. Reaction of aldehyde 3 with lactone 8
Starting from the general scheme of the mechanism proposed for the condensation of aldehydes
with CH-acids in the presence of an alkaline catalyst it can be assumed that attack on the aldehyde
by the RCH2- anion (AnF), formed in the presence of the alkaline catalyst, leads to the
intermediate An, which is converted by adding a proton into the intermediate B. The unsaturated
product 13 is formed as a result of the elimination of water molecule from the intermediate B
(Scheme 5):
Calculation of the potential energy surface of the reaction system, consisting of the
trimethylfuranone 8 and the OH- ion, shows that the formation of the anion AnF takes place
without an energetic barrier. The heat of reaction amounts to -378.9 kJ/mol.
During investigation of the interaction of the molecule of the aldehyde 3 with the anion
AnF it was established that for the formation of the intermediate An the reacting system must
pass through a transition state, overcoming an energy barrier of 90.8 kJ/mol. As shawn by the
calculations, the source of the proton in this case may be complexes representing hydralcd sodium
ions: [H2ONa]1. The intermediate B is also characterized by fairly high proton affinity
(520.0 kJ/mol). The subsequent transformation of the intermediate C depends on the nature of the
attacking nucleophile. During attack by the hydroxyl group the unsaturated product (13) is formed
(path I) (Scheme 6):
Scheme 6. Conversion of protonated aldol C into products 13 and 22
Figure 1 shows the change of structure of the reaction system.
Fig. 1. The transformations of the protonated intermediate C in the reaction with the OH group.
a) Initial state of reaction system;
b) intermediate complex with the C(2) H ( 1 ) OH bridging bond;
c)reaction products: compound 13 and two water molecules. Distances are given in angstrems.
Visualization ofthe process shows that the removal of the first water molecule takes place
when the distance from H(1) to the O of the OH- group decrease to 3.856 Å. With the approach of
the hydroxyl group to a distance of 1.24 Å a bridge C(2) H(1)  OH- structure is formed (Fig. 1b).
The H(1)-C
(2)
bond is then broken, a second water molecule leaves, and compound 13 is formed
(Fig. 1c). The predicted heat of formation of the crotonization product 13 in this path is 973.0 kJ/mol.
The reaction of the anion AnF with the intermediate C (path II) proceed regioselectively
and cause the formation of the two reaction products 13 and 22 depending on the direction of
attack. By attack of the AnF on H(1) atom after approach of the reagents to a distance of 3.671 Å
between the C(2)_ and C(3) atoms, dehydration occurs (Fig.2b). With approach of the RC(3)H2- anion
to the C(2) atom to a distance of 2.806 Å an intermediate complex is initially formed through a
hydrogen bond C(2)H(1)C(3). The C(2)-H(1) bond is then broken, and the product 13 and the
methylfuranone 8 appear (Fig.2c). In this case the heat of formation of the pyridylvinyllactorie 13
is-605.4 kJ/mol.
Fig. 2. The transformations in the reaction of the anion AnF with the H1 atom of the protonated intermediate C.
a) Initial state of reaction system;
b) dehydration of the aldol C;
c) reaction product 13 and furanone 8.
Attack by the anion AnF on the other reaction center of the intermediate C, i.e., the C(1)
atom (Fig. 3a), gives rise to departure of a water molecule on approach of the reagents to a
distance of 2.97 A (Fig. 3b) and the subsequent formation of a compound of the Michael adduct
type 22 (Fig. 3c). The heats of formation of the products 13 and 22 in this case are comparable
(-605.4 and -656.1 kJ/mole respectively), and their appearance must therefore be equally probable
from the thermodynamic standpoint. On the whole (with regard to both paths), the formation of
compound 13 is more probable than the formation of compound 22. In tact, at room temperature
the yield of the crotonization product 13 is higher than the yield of the product 22 (Table 3). If the
temperature is increased to 78°C only compound 13 is formed.
If the transformation of the protonated intermediate C along paths I and II is regarded as
elimination and substitution, it should be noted that the above-mentioned experimental fact agrees
with the idea existing in the literature that the elimination reaction should predominate with
increase of temperature. On the other hand only product 13 is formed if the concentration of the
Fig. 3. The transformations in the reaction of the anion AnF with the C(1) atom of the protonaled
intermediate C.
a) Initial state of reaction system;
b) dehydratation of the intermediate C;
c) reaction products: compound 22 and water molecule.
catalyst is increased to an aldehyde:NaOH ratio of 1:0.3, since (as expected) the rate of the
transformation along path I is increased considerably. At the same time path II becomes more
favorable in the absence of the catalyst, and the main product is compound 22. Thus, the obtained
experimental material favors the proposed model of condensation of the aldehyde 3 with the
lactone 8.
The formation of compound 22 is accompanied by inversion of the configuration of the
tetrahedral carbon atom (Walden inversion), indicating that the reaction takes place by an SN2
mechanism of bimolecular nucleophilic substitution. Figure 4 shows the molecular structure of
compound 22, optimized by the AMI method. According to the calculations, the angle between
the planes of the furan rings amounts to 60°, and the angles between the latter and the plane of the
pyridine ring amount to 161.9 and 121.6°.
In our opinion, the low probability proposed in the literature for the formation of compound 22
by addition of a second molecule of methylfuranone at the double bond of the crotonization
product 13 is also favored by the following. According to the calculated data, compound 13 is
fairly strongly polarized (dipole moment 5.5 D), but the olefinic carbon atoms most likely have an
excess of electron density (their calculated charges are -0.062 and -0.156), which is unfavorable
for the addition of a second anion AnF to the nucleophilic olefin 13. On the other hand, according
to the results of thin-layer chromatography, both products are formed almost simultaneously
under the reaction conditions.
Fig. 4. The three-dimensional structure of the molecule of
Bis-[2-oxo-3-cyano-5,5-dimethyl 2(5h)-furanyl-4-methyl]-3-methylpyridine 22
Thus, quantum-chemical analysis of the mechanism of the condensation of
pyridinecarbaldehyde 3 with furanone 8 shows that the parallel formation of the two reaction
products is possible from one and the same intermediate compound, representing the protonated
product of the aldol condensation of pyridinecarbaldehyde 3 with furanone 8. The reaction of the
intermediate product with the hydroxyl group followed by dehydration leads to the
pyridylvinylfuranone. At the same time the reaction of this intermediate with the
trimethylfuranone anion takes place regiospecificaliy and can lead to the formation of both the
crotonization product and the compound of the Michael adduct type.
2. Condensation of benzaldehydes with 3-cyano-4,6,6-trimethyl-5,6-dihydro-2(5H)pyranone.
The base-catalyzed reaction of benzaldehydes (32-40) with 3-cyano-4,6,6-trimethyl-5,6dihydro-2(5H)-pyranone 10 proceeds also unusually, and is accompanied by the formation of the
Michael-type addition compounds (50-58) along the traditional aldol condensation products (4149) (Scheme 7). The yield of the Michael-type addition product is 60-80%. (Table 4). The yields
of the reaction products were determined by HPLC on a Nova-Pak Silica column (3.9x150 mm)
without isolation.
Scheme 7. Synthesis of helaryl derivatives of -lactones.
In the case of aldehyde 38 reaction with pyranone 11, the Michael-type addition product 56
was not isolated but the 1H NMR spectra showed that this compound is present in the reaction
mixture. The formation of Michael-type addition product 50 occurred independently from molar
ratio of reagents during the reaction of benzaldehyde 32. The yield of pyranone 50 increases
along the increase of the catalyst quantity and reaction time.
Electron donating substituent (aldehyde 36) significantly decreases reaction rate and more
than 76% of pyranone 10 became unchanged. The yield of product 54 was only 1,7%.
We undertook a model quantum chemical investigation of the reaction mechanism by the
AMI method for the case of the reaction of benzaldehyde 33 with pyranone 10 leading to the
product of crotonization 42 and the product of Michael-type addition 51. According to the general
scheme of the mechanism proposed for the condensation of aldehydes with CH-acids it can be
assumed that attack on the aldehyde by the anion, formed in the presence of the alkaline catalyst,
leads to the aldol condensation product.
It was established by us that the interaction of the water molecule (formed during the
deprotonalion of pyranone 10) with Na+ may cause the formation of hydrated sodium ions:
[H2ONa]+. Such complexes may be the source of the protons in the reaction system.
Table 4. Condensation of benzaldehydes with pyranone 10 at 780C
The calculations show that the subsequent transformation of the protonated aldol A depends
on the nature of the attacking nucteophile (Scheme 8).
Scheme 8. Transformation of the protonated aldol A.
During attack by the hydroxyl group the unsaturated product 42 is formed (path 1). OH ion
is directed to the atom H1 along the C(2)-H1 bond. With the approach of the hydroxyl group to a
distance of 2.86 Å the water molecule removes. The elimination of H1 from C(2) atom by OH- ion
results in leaving of the second water molecule and unsaturated compound 42 formation. The
interaction of protonated aldol condensation product with OH - ion takes place without an
activation barrier. The heat of reaction is -1011.7 kJ/mol.
During attack by deprotonated pyrone HetCH(2)- ion (the charge of C(3) atom is -0.386) on the
C(1) atom of intermediate A (the charge is 0.146) the dehydration occurs. With approach of the
C(3) atom to the C(1) atom to a distance of 1.523 Å a compound 51 is formed. Thus, according to
our investigation the products can be formed in parallel from one and the same intermediate
compound. In this case the reaction between deprotonated pyranone and protonated aldol A is not
regiospecific and intermediate lakes part in substitution reaction only. Such mechanism can
explain why the yield of the Michael adduct type 51 are significantly higher than such one found
in the reaction of furanone with of pyridinecarboxaldehyde 3.
The biological activity of organic compounds usually depends on their geometrical
configuration. The investigation employing a semiempirical AM1 method to calculate the EZ
photoisomerization process of pyranone 42 and structures of both isomers was undertaken.
Optimum geometries of isomers in a ground and two lowest excited states (singlet and. triplet)
were found. Structural, electronic and energetic characteristics were estimated.
It has been established that the E-isomer is more stable in ground slate than Z-isomer. The
energy of S(0)  S(1), transition is higher for Z-isomer. Such a conclusion means that in the case
of photostationary state Z-isomer will be predominant in the reaction system. This result of
quantum chemical calculation is in agreement with experimental data. Kinetics experiments
indicate that under influence of the visible light aproximately 80% of E-pyranone 42 changes
into Z-isomer (Fig. 5a).
Simulated spectra of E- and Z-isomers are built using biGauss band shape (Fig. 5 b) and
compared with UV absorption spectra of pyranone 42.There is a good coincide of theoretical and
experimental spectra. It is suggested on the basis of the findings that E  Z photoisomerization of
pyranone 42 occurs via singlet state (a singlet mehanism).
Fig. 5. UV spectra of pyranone 42 : a) in ethanol solution (I, E-isomer) and after lighting
with visible light for 3 h (II, the mixture of 20% of E- isomer + 80% of Z-isomer); b) simulated
UV spectra of E-isomer (HI), of Z-isomer (IV), of the mixture of 20% E- + 80% Z-isomer (V).
3. Biological Activity of Aryl (Hetaryl ) y- and -Lactones
Computer screening has been made using OREX expert system for the study of structureactivity relationships of the set of unsaturated aryl (hetaryl) lactones. OREX system was
elaborated in the Latvian Institute of Organic Synthesis. Anticancer, antibacterial and
cardiostimulating activities have been predicted by OREX for lactones studied. In the course of
the computer analysis we get the list of possible pharmacological and therapeutical activities.
Table 5 includes descriptors of the basically cardiovascular activities.
The derivatives of unsaturated - and -lactones have been tested in vivo and ex vivo. Table 6
summarizes the data of the antiarrhythmic screening test and acute toxicity obtained for the
compounds synthesized.
The acute toxicity of the studied compounds was low (LD50 was over 400 mg/kg). Only the
acute toxicity of compound 14 (LD(50) l80 mg/kg) and 15 (200 mg/kg) was comparable with that of
Lidocaine - LD50 238 mg/kg. On the whole the five-membered pyridyl lactones 12-16 had the
toxicity similar to their six-membered analogues except compounds 13 and 14, the toxicity of
which was about 2-fold higher than that of the substituted pyranones. The pyridyl substituents of
pyridyl lactones are responsible for a higher toxicity in comparison with quinolyl lactones. The
antiarrhythmic activity of furanone 16 was higher, but its toxicity lower than that of Procainamide
reference drug.
Table 5. Descriptors of cardiovascular activities.
Table 6. Anliarrhythmic activity and acute toxicity of pyridyl laclones in mice.
The activity depended on the position of a substituent in heterocycle. The most active are 4isomers - compounds 14 and 19. The replacement of 4-pyridyl substituent of furanone for 4quinolyl group decreased the antiarrhythmic activity. A similar replacement in the case of 4pyridylpyranone caused the activity increase. Pyridyl and quinolyl lactones caused a significant
protection against CaCl(2)-induced arrhythmia (Table 7).
Table 7. Effect of compounds 13 un 14 on CaCl(2)-mduced arrhythmia and lethality in rats
Cardiotonic and vasodilating properties of hetaryl lactones were also studied on
anaesthetized cats. Compounds 16, 19 and 28 induced a significant vasodilating activity at a
concentration 50 M (furanone 16 being the most active). The vasodilaling activity depended on
the lactone nature as well as on a hetaryl substituent nature and its isomerism. Six-membered
lactones revealed more pronounced vasodilatation than five-membered ones. On the other hand, 2pyridylfuranone and 2-pyridylpyrone demonstrated more marked vasodilatation than 3- and 4isomers. Besides, this 2-pyridylfuranone at the same time also possessed vasoconstriction. The
introduction of a second vinyl group in the aliphatic chain between the pyridine and lactone rings
strengthened the activity of pyridyl furanone, and thus furanone 16 being the most active among
the compounds studied.
The vasodilaling effect of a nitrophenyl substituent is similar to that of a pyridyl substituent.
Cardiotonic activity is more pronounced for 3- and 4-isomers of pyridyl furanones. Cardiotonic
activity of the corresponding 6-membered lactones is lower.
Five-membered lactones, particularly furanones 13 and 14, exhibited a remarkable
cardiotonic activity. 4-Pyridyl lactone 14 (dose = 0.5 mg/kg) increased the sistolic pressure of the
left ventricle by 30%, but dP/dt by 32%, and the mean arterial blood pressure by 18%.
The replacement of a pyridyl substituent by a nitrophenyl group in the pyranone derivative
does not change the cardiovascular activity and toxicity.
Antitumor activity was predicted for the synthesized compounds also. Below the examples
of the prediction descriptors for antitumor activity are shown (Fig. 6):
Fig. 6. Prediction of the activity using OREX ekspert-system.
The descriptor which can be responsible for the possessing antitumor activity includes the
fragments of furanone 19 molecule between two N atoms. The compounds consisting of
furanone 8 and benzene structures at the appointed distance could be inhibitors of kinase and
polymerase.
Lactones synthesized were tested for cytotoxic properties in vitro on monolayer mouse
tumor cell lines: MG-22A (hepatoma), B16 (melanoma), Neuro2A (neuroblastoma). Cells were
cultivated in DMEM standard medium without an indicator in 96 wells plates for 72 h. Ceils
seeding concentration were 2-5x104 cells/ml (depending on line nature). A quantity of survived
cells were determined using crystal violet (CV) and 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) coloration. Concentration of NO' in plate wells was
determined according Griess reaction.
Structure-activity relationship for the cytotoxic action on cell line MG-22A indicates the
preference of the five-membered lactone 19 in comparison with compounds containing sixmembered lactone 28 moiety (Table 8.).
Table 8. In vitro cell cytotoxicity and the ability of NO generation caused by some
unsaturated lactonesa. Monolayer mouse tumor cell line: MG-22A (hepatoma).
Furanone 19 showed selective activity against Neuro2A cells. (Table 9). The activity of
compound 19 (TD5o, CV) decreases in the following sequence: Neuro2A>MG-22A>B16.
Table 9. Cytotoxic activity of the compound 19 against different tumor cell lines.
Four lactones synthesized (25, 28, 43 and 52) significantly stimulate the nitric oxide
biosynthesis in cells at low concentration. Lactone 43 possess higher activity.
Conclusions
1. Reaction of the aryl (hetaryl) aldehydes with 3-cyano-4,5,5-trimethy 1-2(5H)-furanone, 3carbethoxy-4,5,5-trimethyl-2(5H)-furanone and 4,6,6-trimethyl-3-cyano-(5,6-dihydro)-2pyranone in the presence of catalytic quantity of NaOH takes place by an untraditional
mechanism, and compounds of the Michael adduct type are formed together with the
product of crolonization.
2. Quantum-chemical analysis of the condensation mechanism shows that the parallel
formation of the two reaction products is possible from one and the same intermediate
compound, representing the protonated product of the aldol condensation of aldehyde with
lactone.
3. When exposed to the visible light, hetaryl(aryl) vinyl derivatives undergo E-Z
photoisomerization.
3-Cyano-4-(4-nitrophenylvinyl)-6,6-dimethyl-(5,6-dihydro)-2(2H)-
pyranone, applying as a model compound, quantum-chemical semiempirical AMI method
shows, that in the ground state E- isomer is more stable thermodynamically than Z-isomer.
E-Z photoisomerization process, probably proceeds in the lower excited singlet state S1. of
lactones studied occurs via singlet state (a singlet mehanism).
4. The computer screening using OREX expert system has been performed. It was predicted
that new lactone synthesized could have cardiovascular and anticancer activities.
5. The antiarrhythmic, vasodilating and cardiotonic activities of the synthesized compounds
have been studied in vivo and ex vivo.
butadienyl)]-2(5H)-furanone)
displayed
3-Cyano-5,5-dimethyl-4-[4'-(4-pyridyl)-1',3'a
significant
vasodilating
activity.
The
antiarrhythmic activity of this compound was higher, but its toxicity lower than that of
Procainamide reference drug.
3-Cyano-4-(4-pyridylvinyl)-5,5-dimethyl-2(5H)-furanone,
exhibited a remarkable cardiotonic activity.
6. Investigations of Iactones in vitro on monolayer mouse tumor cell lines shows that
furanones exhibited higher activity than pyrones. 3-Cyano-4-[(4-quinolyl)vinyl]-5,5dimethyl-2(5H)-furanone,
pyranone
and
3-Cyano-4-(4-nitrophenylvinyl)-6,6-dimethyl-5,6-dihydro-2-
3-Cyano-4-(4-chlorphenylvinyl)-6,6-dimethyl-5,6-dihydro-2-pyranone
possess marked cytotoxic activity. 3-Cyano-4-(4-chlorphenylvinyl)-6,6-dimethyl-5,6-dihydro2-pyranone in low concentration significantly stimulates the nitric oxide biosynthesis in
cells.
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