Novel dihydropyridine thioglycosides and their corresponding dehydrogenated forms as potent anti-hepatocellular carcinoma agents

Nucleosides, Nucleotides and Nucleic Acids

ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20

Novel dihydropyridine thioglycosides and their

corresponding dehydrogenated forms as potent

anti-hepatocellular carcinoma agents

Galal H. Elgemeie & Dina H. El-Naggar

To cite this article: Galal H. Elgemeie & Dina H. El-Naggar (2018): Novel dihydropyridine

thioglycosides and their corresponding dehydrogenated forms as potent anti-

hepatocellular carcinoma agents, Nucleosides, Nucleotides and Nucleic Acids, DOI:

10.1080/15257770.2018.1457161

To link to this article: https://doi.org/10.1080/15257770.2018.1457161

Published online: 03 May 2018.

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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

, VOL. , NO. , –

https://doi.org/./..

Novel dihydropyridine thioglycosides and their

corresponding dehydrogenated forms as potent

anti-hepatocellular carcinoma agents

Galal H. Elgemeie^aand Dina H. El-Naggar^b

^aDepartment of Chemistry, Faculty of Science, Helwan University, Helwan, Cairo, Egypt; ^bDepartment of

Applied Organic Chemistry, National Research Center, Giza, Egypt

ABSTRACT

ARTICLE HISTORY

Received  April 

Revised  March 

Accepted  March 

A novel method for preparation of a new class of dihydropyridine

thioglycosides and their corresponding dehydrogenated forms,

via reaction of piperidinium salts of dihydropyridinethiones with

2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides

has been studied. The evaluation of antiproliferative activity

against HepG-2 cell lines (liver carcinoma cell lines) of the dihy-

dropyridine thioglycosides and pyridine thioglycosides revealed

that many of the thioglycosides have interesting antitumor activ-

ities speciﬁcally 5c, 5g, 5l, 5o, 5p, 7a, 7i, 7p, 8b, 8f, 8s, and 8v.

KEYWORDS

dihydropyridinethiones;

dihydropyridine

thioglycosides;

pyridinethiones; pyridine

thioglycosides;

antimetabolites

Introduction

In recent years nucleoside analogues have occupied a signiﬁcant position in the

search for eﬀective antiviral agents, owing to the fact that a large number of

unnatural nucleoside derivatives have been shown to inhibit infection caused by

viruses.^[1,2]The heterocyclic thioglycosides constitute a class of analogues with

potential biological activity.^[3–12]In recent reports from our laboratory, we described

the preparation of diﬀerent novel functionalized pyridinethione glycosides, which

revealed antagonistic activity against human carcinoma cells and HIV.^[13]In an ear-

lier brief communication we had reported the use of dihydropyridinethione glyco-

sides as P-glycoprotein (Pgp) substrates or inhibitors in the protein glycosylation

process.^[14]These common features encouraged us to develop a new straightfor-

ward route for the synthesis of these compounds. In the present report, we describe

the synthesis of dihydropyridine thioglycosides through reaction of piperidinium

salts of dihydropyridinethiolates with δ-acetylated α-glycosyl halides.

Results and discussion

It has been found that arylmethylidenecyanothioacetamide 1 reacted with

3-oxo-N-arylbutanamides 2 in ethanol containing piperidine at 0°C to give the

CONTACT Galal Elgemeie

sity, Helwan, Cairo, Egypt.

elgemeie@yahoo.com

Chemistry Department, Faculty of Science, Helwan Univer-

Color versions of one or more of the ﬁgures in the article can be found online at www.tandfonline.com/lncn.

2

G. ELGEMEIE AND D. H. EL-NAGGAR

Table . Cytotoxcity of the synthesized compounds a-v, a-v and a-v on liver (HEPG) cancer cell

lines.

Compound no.

IC_(µg/mL)

Compound no.

IC_(µg/mL)

Compound no.

IC_(µg/mL)

5a

5b

5c

5d

5e

5f

5g

5h

5i

5j

5k

5l

5m

5n

5o

5p

5q

5r

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

7a

7b

7c

7d

7e

7f

7g

7h

7i

7j

7k

7l

7m

7n

7o

7p

7q

7r

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

8a

8b

8c

8d

8e

8f

8g

8h

8i

8j

8k

8l

8m

8n

8o

8p

8q

8r

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

5s

5t

5u

5v

(5FU)^b

7s

7t

7u

7v

(5FU)^b

8s

8t

8u

8v

(5FU)^b

.

.

.

.

.

.



corresponding piperidinium salts of 1,4-dihydropyridine-2-thiones 3 (Chart 1).

The structures of salts 3 was established on the basis of their elemental analysis

and spectral data. Compounds 3 react with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and

galacto-pyranosyl bromides in acetone at 0°C to give in a high yield the corre-

sponding S-glucosides 5a-p or S-galactosides 5q-v, respectively. The structures of

the reaction products 5a-v were established by their elemental analyses and spectral

data (IR, ¹H NMR, ¹³C NMR). As an example, the analytical data for 5l revealed a

IC50 (µg/mL)

30

25

20

15

10

5

IC50 (µg/mL)

0

Figure . Cytotoxcity of the synthesized acetyled dihydropyridine thioglycosides 5a-v on liver

(HEPG) cancer cell line.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

3

IC50 (µg/mL)

30

25

20

15

10

5

IC50 (µg/mL)

0

Figure . Cytotoxcity of the synthesized acetylated pyridine thioglycosides 7a-v on liver (HEPG) can-

cer cell line.

molecular formula C₃₅H₃₆ClN₃O₁₁S. The ¹H NMR spectrum showed the anomeric

ꢀ

proton as a doublet at δ 5.34 ppm. The coupling constant J_{1 ,2}= 9.6 Hz indicated

H-1^ꢀto be trans-diaxial to H-2^ꢀ. The other six glucose protons resonated at 3.69–

4.92 ppm and the four acetyl groups appeared as four singlets at δ 1.93–2.05 ppm.

The ¹³C NMR spectrum of 5l contained a signal at δ 82.8 corresponding to the C-1^ꢀ

atom and ﬁve signals appearing at δ 61.9, 67.8, 70.2, 72.7 and 75.0 that were assigned

to C-6^ꢀ, C-4^ꢀ, C-2^ꢀ, C-3^ꢀand C-5^ꢀ, respectively. The formation of S-glycosides 5

and not the corresponding N-glycosides 6 (chart 1) were proved using ¹³C NMR

spectroscopy, which revealed the absence of the thione carbon at δ 178 ppm and

the appearance of a signal at δ 160 ppm corresponding to the C-2 carbon, whose

IC50 (µg/mL)

30

25

20

15

10

5

IC50 (µg/mL)

0

Figure . Cytotoxcity of the synthesized free pyridine thioglycosides a-v on liver (HEPG) cancer cell

line.

4

G. ELGEMEIE AND D. H. EL-NAGGAR

CN

O

Ar₁

S

+

Ar₂HN

CH₃

NH₂

1a-d

2a-d

EtOH/piperidine

0 ^o

C

Ar₁

O

CN

S

Ar₂HN

CH₃

N

H

N

H

3

AcO

R¹

R²

O

OAc

Ar₁

O

CN

Ar₂HN

Br

OAc

CH₃

N

SH

II

4

acetone / 0 ^o

C

AcO

R¹

O

OAc

R²

OAc

6

O

Ar₁

CN

S

Ar₂HN

CH₃

N

H

AcO

R¹

O

OAc

R²

OAc

5a-v

1

Ar₁

2

Ar₂

a,

b,

c,

d,

C₆H₅

a,

b,

c,

d,

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

Scheme . A synthetic pathway for dihydropyridine thioglycosides a-v.

chemical shift is the same as that of the corresponding S-methyl derivative.^[15]In

another experiment, the piperidinium salts 3 reacted with 2,3,4,6-tetra-O-acetyl-α-

D-gluco- and galactopyranosyl bromides in acetone at 30°C (chart 2) to aﬀord the

corresponding aromatized pyridine thioglucosides 7a-p and thiogalactosides 7q-v.

Compounds 7 could also be prepared by heating dihydro thioglycosides 5 in ethanol

for 3 minutes, which underwent spontaneous auto-oxidation to aﬀord the aroma-

tized thioglycosides 7. The structures of the reaction products 7a-v were established

and conﬁrmed on the basis of their elemental analyses and spectral data (IR, ¹H

NMR, ¹³C NMR). When glycosides 7 were treated with methanolic ammonia at

room temperature, the free glycoside derivatives 8a-v were obtained, the structures

of which were established on the basis of elemental analysis and spectral data.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

5

Ar₁

O

CN

S

Ar₂HN

2

1

+

N

CH₃

N

H

3

EtOH / pip.

AcO

R¹

R²

O

OAc

O

Ar

Br

OAc

CN

4

Ar₂HN

acetone / 30 ^o

C

CH₃

N

S

H

9a-P

Ar₁

O

Ar₁

O

CN

S

CN

S

Ar₂HN

AcO

Ar₂HN

R¹

R²

O

CH₃

N

CH₃

N

H

OAc

Br

OAc

AcO

R¹

aq. KOH

acetone / 30 ^oC

AcO

R¹

EtOH /

3 min

4

O

OAc

O

OAc

R²

OAc

7a-v

5a-v

NH₃/ CH₃OH

Ar₁

O

CN

Ar₂HN

CH₃

N

S

HO

R¹

R²

O

OH

8a-v

Scheme . Synthetic pathways for pyridine thioglycosides a-v, a-v.

Thus, the analytical data for 8e revealed a molecular formula C₂₇H₂₇N₃O₆S. The

¹H NMR spectrum showed the anomeric proton as a doublet at δ 5.58 ppm (J_{1 ,2}

=

ꢀ

9.8 Hz) indicating a β-D-conﬁguration. The signals of the other six glucose protons

appeared as a multiplet at δ = 3.17–3.66 ppm, while the signals that are disappeared

on rapid exchange with D₂O and are observed at δ 4.47–5.23 ppm were assigned as

the four hydroxy groups, the ¹³C NMR spectrum of 8e is characterized by a signal at

δ = 82.3 ppm corresponding to the C-1^ꢀand ﬁve other signals at δ 59.4, 68.4, 70.4,

77.3 and 80.4 ppm that are assigned to C-6^ꢀ, C-4^ꢀ, C-2^ꢀ, C-3^ꢀand C-5^ꢀ, respectively.

Encouraged by these results, we decided to synthesize the pyridine thioglycosides 7

using the silylation method and comparing the resulting products for stereochemi-

cal considerations. Thus, in a simple experimental procedure (Chart 4) treatment of

the piperidinium salts 3 with dilute hydrochloric acid at 30°C converted them to the

corresponding pyridine-2(1H)thiones 9. The latter compounds were reacted with

hexamethyldisilazane (HMDS) in the presence of ammonium sulfate to give the cor-

responding 2-trimethylsilylthiopyridines 11, which were subsequently treated with

peracetylated sugars 13 in the presence of redistilled SnCl₄to aﬀord the S-glycosyl

compounds 7 (Chart 5). The latter were shown to be the same as those obtained from

the reaction of 3 with 4 by comparison of their melting points and spectral data.

6

G. ELGEMEIE AND D. H. EL-NAGGAR

5,7

a,

b,

c,

d,

e,

f,

g,

h,

i,

j,

k,

l,

m,

n,

o,

p,

q,

r,

s,

Ar₁

Ar₂

R¹

H

R²

C₆H₅

OAc

H

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

C₆H₅

4-H₃CO-C₆H₄

4-Cl-C₆H₄

H

C₆H₅

H

C₆H₅

H

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

H

OAc

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

H

t,

u,

v,

H

8

Ar₁

Ar₂

R¹

H

R²

OH

H

a,

b,

c,

d,

e,

f,

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

H

C₆H₅

H

C₆H₅

H

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-Cl-C₆H₄

C₆H₅

H

g,

h,

i,

j,

k,

l,

m,

n,

o,

p,

q,

r,

s,

t,

u,

v,

H

OH

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

4-H₃C-C₆H₄

4-H₃CO-C₆H₄

C₆H₅

4-H₃CO-C₆H₄

4-Cl-C₆H₄

H

Scheme . List of synthesized derivatives a-v, a-v, a-v.

Anti proliferative activity study

The in vitro anti-hepatocellular carcinoma (anti-HCC) activity of the newly syn-

thesized dihydropyridine thioglycosides and pyridinethioglycosides was examined

against the HepG2 cell line using the MTT method.^[16]5FU, which is one of the

most eﬀective anticancer agents was used as positive control. The activity was

expressed by median growth inhibitory concentration (IC₅₀) and was provided

in T able 1. The results revealed that many of the synthesised dihydropyridine

and pyridine thioglycosides exhibited antiproliferative activity with IC₅₀values

ranging from 8.5–22.5 µg/ml. Thioglycoside compounds 5c, 5g, 5l, 5o, 5p, 7a,

7i, 7p, 8b, 8f, 8s, and 8v possessed activity at low microgram levels (IC₅₀= 10.2,

10.4, 9.5, 12.5, 8.5, 9.0, 8.1, 8.9, 10.2, 8.7, 11.8 and 8.9 µg/ml, respectively), which

were shown in (Figures 1–3). The diﬀerent substituents on phenyl and carbamoyl

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

7

HCl / 30 ^o

C

CH₃I / 30 ^o

C

3

Ar₁

O

Ar₁

N

O

CN

CH₃I

KOH/ CH₂Cl₂

CN

Ar₂HN

CH₃

N

H

S

CH₃

SCH₃

10a,b

9

HMDS

(NH₄)₂SO₄

EtOH/

Ar₁

O

Ar₁

CN

O

CN

Ar₂HN

CH₃

N

H

SCH₃

CH₃

N

S-Si(CH₃)₃

11

12a,b

AcO

R¹

OAc

O

CH₃I / 0 ^o

C

OAc

R²

13 OAc

SnCl₄/ CH₃CN

3

7a-v

10,12

a,

Ar₁

Ar₂

4-H₃C-C₆H₄

4-Cl-C₆H₄

C₆H₅

b,

Scheme . Synthetic pathways for a,b; a,b.

moieties at positions 4 and 5 of pyridine ring were responsible for the variation

the cytotoxic activity. The acetylated dihydropyridine thioglycoside series with

4-chlorophenyl and 4-chlorophenyl carbamoyl moieties at positions 4 and 5 5c

displayed the best inhibitory activity (IC₅₀= 8.5 µg/ml). Compounds of the acety-

lated pyridine thioglycoside series with 4-methoxyphenyl and phenyl carbamoyl

at positions 4 and 5 7i showed the higher inhibitory activity (IC₅₀= 8.1 µg/ml).

The free pyridine thioglycoside series with 4-methylphenyl and methylphenyl

carbamoyl moieties at positions 4 and 5 8f displayed the best inhibitory activity

(IC₅₀= 8.7 µg/ml).

Conclusion

In summary, we have achieved a novel synthesis of interesting nonclassical dihy-

dropyridine thioglycosides and their corresponding aromatized forms by the

reaction of the piperidinium salts of dihydropyridinethiones with δ-acetylated

8

G. ELGEMEIE AND D. H. EL-NAGGAR

α-glycosyl halides, the nature of the products depending upon thermodynamic

factors. These glycosides can be utilized as excellent starting materials for the

synthesis of other carbohydrate derivatives and for further biological evaluation

studies.

Experimental

All evaporations were carried out under reduced pressure at 40°C M.p.s are uncor-

rected. Aluminum sheets coated with silica gel F₂₅₄(Merck) were used for TLC.

Detection was eﬀected by viewing under a short-wavelength UV lamp. IR spectra

were obtained (KBr disk) on a Pye Unicam spectra 1000. ¹H NMR and ¹³C NMR

spectra were measured on a Wilmad 270 MHz or on a Vairan 400 MHz spectrome-

ter for solution in CDCl₃or (CD₃)₂SO with SiMe₄as internal standard. J Values are

given in Hz. Analytical data were obtained from the Microanalytical Data Center at

Cairo University.

4-Aryl-3-cyano-6-methyl-2-(2,3,4,6-tetra-O-acetyl-β-D-gluco- and galacto-pyra-

nosylthio)-1,4-dihydropyridines (5a-v)

General procedures

A mixture of 1a-d (0.01 mol) and 2a-d (0.01 mol) was dissolved in dry ethanol

(5 ml), and then piperidine (0.01 mol) was added. The reaction mixture was stirred

at 0°C for 1 h and then left to stand to room temperature. The solvent was removed

at reduced pressure and the resulting piperidinium salt of 1,4-dihydropyridine-2-

thione 3 was dissolved in dry acetone (5 ml) and a solution of 2,3,4,6-tetra-O-acetyl-

α-D-gluco- or galactopyranosyl bromide (0.01 mol) in dry acetone (20 ml) was then

added at 0°C. The reaction mixture was stirred until the reaction was judged com-

plete by TLC, using chloroform:ether 4:1 (Rf, 0.68–0.72), then concentrated under

reduced pressure and the residue crystallized from chloroform-petroleum ether at

0°C.

5a: yellow, mp: 158°C; yield: (81%). Anal. Calcd. for (C₃₄H₃₅N₃O₁₀S): C, 60.26;

H, 5.16; N, 6.20. Found: C, 60.71; H, 5.02; N, 6.35.

5b: yellow, mp: 155°C; yield: (80%); IR.: ν_max/Cm⁻¹(KBr) 3312 (NH); 2191(CN);

1750 (CO); 1655 (CO). Anal.: Calcd. for (C₃₅H₃₇N₃O₁₀S): C, 60.78; H, 5.35; N, 6.07.

Found: C, 60.42; H, 5.72; N, 6.38.

5c: yellow, mp: 153°C; yield: (86%); IR.: ν_max/Cm⁻¹(KBr) 3412 (NH); 2185 (CN);

1750 (CO). Anal. Calcd. for (C₃₅H₃₇N₃O₁₁S): C, 59.40; H, 5.23; N, 5.94.

Found: C, 59.83; H, 5.65; N, 6.01.

5d: yellow, mp: 222°C; yield: (80%); IR.: ν_max/Cm⁻¹(KBr) 3372 (NH); 2186(CN);

1748 (CO); 1671 (CO). Anal. Calcd. for (C₃₄H₃₄ClN₃O₁₀S): C, 57.34; H, 4.77; N,

5.90. Found: C, 57.79; H, 4.93; N, 5.79.

5e: pale yellow, mp: 197°C; yield: (85%); IR.: ν_max/Cm⁻¹(KBr) 3370 (NH); 2202

(CN); 1752 (CO); 1669 (CO). Anal. Calcd. for (C₃₅H₃₇N₃O₁₀S): C, 60.78; H, 5.35;

N, 6.07. Found: C, 61.15; H, 5.02; N, 6.39.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

9

5f: pale yellow, mp: 160°C; yield: (81%); IR.: ν_max/Cm⁻¹(KBr) 3370 (NH); 2202

(CN); 1752 (CO); 1667 (CO). Anal. Calcd. for (C₃₆H₃₉N₃O₁₀S): C, 61.27; H, 5.53;

N, 5.95. Found: C, 61.11; H, 5.49; N, 6.15.

5g: yellow, mp: 191°C; yield: (83%); IR.: ν

/Cm⁻¹(KBr) 3422 (NH); 2226

max

(CN); 1752 (CO); 1642 (CO). Anal. Calcd. for (C₃₆H₃₉N₃O₁₁S): C, 59.91; H, 5.40;

N, 5.82. Found: C, 60.25; H, 5.56; N, 5.41.

5h: pale yellow, mp: 180°C; yield: (81%); IR.: ν_max/Cm⁻¹(KBr) 3361 (NH); 2202

(CN); 1753 (CO); 1671 (CO); ¹H NMR: δ 1.96–2.08 (4s, 12H, 4CH₃CO); 2.20 (s,

H

3H, CH₃); 2.41 (s, 3H, CH₃); 4.01 (m, 2H, 2H-6^ꢀ); 4.17 (m, 2H, H-5^ꢀand pyridine

H-4); 4.79 (d, 1H, H-4^ꢀ); 4.91 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.34 (d, J_{1 ,2}= 9.8 Hz, 1H,

H-1^ꢀ); 7.10–7.61 (m, 8H, 2C₆H₄); 8.70 (bs, 1H, NH); 9.76 (bs, 1H, NH). Anal. Calcd.

for (C₃₅H₃₆ClN₃O₁₀S): C, 57.89; H, 4.96; N, 5.78. Found: C, 57.99; H, 5.17; N, 5.66.

5i: yellow, mp: 170°C; yield: (82%); IR.: ν_max/Cm⁻¹(KBr) 3388 (NH); 2200 (CN);

1752 (CO). Anal. Calcd. for (C₃₅H₃₇N₃O₁₁S): C, 59.40; H, 5.23; N, 5.94.

Found: C, 59.67; H, 5.38; N, 6.01.

ꢀ

5j: yellow, mp: 175°C; yield: (85%); IR.: ν_max/Cm⁻¹(KBr) 3370 (NH); 2201 (CN);

1752 (CO); 1665 (CO). Anal. Calcd. for (C₃₆H₃₉N₃O₁₁S): C, 59.91; H, 5.40; N, 5.82.

Found: C, 59.68; H, 5.57; N, 5.49.

5k: yellow, mp: 214°C; yield: (80%); IR.: ν

/Cm⁻¹(KBr) 3386 (NH); 2203

max

(CN); 1752 (CO). Anal. Calcd. for (C₃₆H₃₉N₃O₁₂S): C, 58.61; H, 5.29; N, 5.69.

Found: C, 58.85; H, 5.18; N, 5.83.

5l: yellow, mp: 165°C; yield: (82%); IR.: ν_max/Cm⁻¹(KBr) 3378 (NH); 2201 (CN);

1752 (CO); ¹H NMR: δ 1.93–2.05 (4s, 12H, 4CH₃CO); 2.20 (s, 3H, CH₃); 3.55 (s,

H

3H, OCH₃); 3.69 (m, 2H, 2H-6^ꢀ); 4.0 (m, 2H, H-5^ꢀand pyridine H-4); 4.78 (d, 1H, H-

ꢀ

4^ꢀ); 4.92 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.34 (d, J_{1 ,2}= 9.6 Hz, 1H, H-1 ); 6.80–7.63 (m, 8H,

ꢀ

2 C₆H₄); 8.60 (bs, 1H, NH); 9.74 (bs, 1H, NH);¹³C NMR: δ 20.3–21.6 (4CH₃CO);

C

22.2 (CH₃); 55.0 (OCH₃); 61.9 (C-6^ꢀ); 67.8 (C-4^ꢀ); 70.2 (C-2^ꢀ); 72.7 (C-3^ꢀ); 75.0

(C-5^ꢀ); 82.8 (C-1^ꢀ); 90.9 (C-4); 107.3 (C-3); 114.0 (CN); 120.2–137.9 (2Ar-C); 139.4

(C-5); 140.1 (C-6); 158.4 (C-2); 169.0–170.1 (4CO of glucose); 182.0 (CO of pyri-

dine). Anal. Calcd. for (C₃₅H₃₆ClN₃O₁₁S): C, 56.64; H, 4.85; N, 5.66. Found: C,

56.48; H, 4.63; N, 5.98.

5m: yellow, mp: 175°C; yield: (80%); IR.: ν

/Cm⁻¹(KBr) 3370 (NH);

max

2202(CN); 1752 (CO); 1666 (CO); ¹H NMR: δ 1.93–2.05 (4s, 12H, 4CH₃CO); 2.52

H

(s, 3H, CH₃); 4.02 (m, 2H, 2H-6^ꢀ); 4.14 (m, 2H, H-5^ꢀand pyridine H-4); 4.87 (d,

1H, H-4^ꢀ); 5.00 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.37 (d, J_{1 ,2}= 9.7 Hz, 1H, H-1^ꢀ); 6.99–7.54

(m, 9H, C₆H₄and C₆H₅); 8.82 (bs, 1H, NH); 9.71 (bs, 1H, NH). Anal. Calcd. for

(C₃₄H₃₄ClN₃O₁₀S): C, 57.34; H, 4.77; N, 5.90.

ꢀ

Found: C, 57.73; H, 4.93; N, 5.77.

5n: yellow, mp: 241°C; yield: (85%); IR.: ν

/Cm⁻¹(KBr) 3381 (NH); 2202

max

(CN); 1752 (CO); 1669 (CO); ¹H NMR: δ 1.98–2.04 (4s, 12H, 4CH₃CO); 2.23 (s,

H

3H, CH₃); 2.51 (s, 3H, CH₃); 3.96 (m, 2H, 2H-6^ꢀ); 4.17 (m, 2H, H-5^ꢀand pyridine

H-4); 4.85 (d, 1H, H-4^ꢀ); 4.99 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.36 (d, J_{1 ,2}= 9.6 Hz, 1H,

H-1^ꢀ); 7.04–7.44 (m, 8H, 2C₆H₄); 8.84 (bs, 1H, NH); 9.61 (bs, 1H, NH). Anal. Calcd.

for (C₃₅H₃₆ClN₃O₁₀S): C, 57.89; H, 4.96; N, 5.78. Found: C, 58.11; H, 4.72; N, 5.91.

ꢀ

10

G. ELGEMEIE AND D. H. EL-NAGGAR

5o: yellow, mp: 195°C; yield: (81%); IR.: ν

/Cm⁻¹(KBr) 3321 (NH); 2202

max

(CN); 1752 (CO). Anal. Calcd. for (C₃₅H₃₆ClN₃O₁₁S): C, 56.64; H, 4.85; N, 5.66.

Found: C, 56.97; H, 4.59; N, 5.87.

5p: yellow, mp: 173°C; yield: (84%); IR.: ν

/Cm⁻¹(KBr) 3371 (NH); 2202

max

(CN); 1752 (CO); 1647 (CO);¹H NMR: δ 1.89–2.04 (4s, 12H, 4CH₃CO); 2.20 (s,

H

3H, CH₃); 3.96 (m, 2H, 2H-6^ꢀ); 4.22 (m, 2H, H-5^ꢀand pyridine H-4); 4.85 (d, 1H, H-

4^ꢀ); 4.89 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.35 (d, J_{1 ,2}= 9.8 Hz, 1H, H-1 ); 6.99–7.64 (m, 8H,

ꢀ

2C₆H₄); 8.80 (bs, 1H, NH); 9.80 (bs, 1H, NH); ¹³C NMR: δ 20.4–21.6 (4CH₃CO);

C

30.6 (CH₃); 60.7 (C-6^ꢀ); 68.1 (C-4^ꢀ); 71.8 (C-2^ꢀ); 73.8 (C-3^ꢀ); 75.5 (C-5^ꢀ); 89.8 (C-1^ꢀ);

94.0 (C-4); 108.8 (C-3); 115.0 (CN); 121.2–131.9 (2Ar-C); 137.7 (C-5); 142.2 (C-6);

157.0 (C-2); 166.0–170.0 (4CO of glucose); 182.0 (CO of pyridine). Anal. Calcd. for

(C₃₄H₃₃Cl₂N₃O₁₀S): C, 54.69; H, 4.42; N, 5.63. Found: C, 54.22; H, 4.87; N, 5.38.

5q: yellow, mp: 215°C; yield: (80%). Anal. Calcd. for (C₃₄H₃₅N₃O₁₀S): C, 60.26;

H, 5.16; N, 6.20. Found: C, 60.07; H, 5.42; N, 6.37.

5r: yellow, mp: 249°C; yield: (80%); IR.: ν_max/Cm⁻¹(KBr) 3386 (NH); 2201 (CN);

1752 (CO). Anal. Calcd. for (C₃₆H₃₉N₃O₁₀S): C, 61.27; H, 5.53; N, 5.95.

Found: C, 61.39; H, 5.71; N, 5.58.

5s: yellow, mp: 189°C; yield: (80%); IR.: ν_max/Cm⁻¹(KBr) 3366 (NH); 2201 (CN);

1752 (CO); ¹H NMR: δ 1.91–2.07 (4s, 12H, 4CH₃CO); 2.15 (s, 3H, CH₃); 2.24 (s,

H

3H, CH₃); 3.61 (s, 3H, OCH₃); 3.69 (m, 2H, 2H-6^ꢀ); 4.01 (m, 2H, H-5^ꢀand pyridine

H-4); 4.78 (d, 1H, H-4^ꢀ); 5.00 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.31 (d, J_{1 ,2}= 9.7 Hz, 1H,

H-1^ꢀ); 6.80–7.45 (m, 8H, 2C₆H₄); 8.72 (bs, 1H, NH); 9.48 (bs, 1H, NH). Anal. Calcd.

for (C₃₆H₃₉N₃O₁₁S): C, 59.91; H, 5.40; N, 5.82. Found: C, 60.22; H, 5.29; N, 6.03.

ꢀ

5t: yellow, mp: 233°C; yield: (84%); IR.: ν_max/Cm⁻¹(KBr) 3437 (NH); 2200 (CN);

1

1752 (CO); 1664 (CO); H NMR: δ 1.97–2.07 (4s, 12H, 4CH₃CO); 2.42 (s, 3H,

H

CH₃); 3.65 (s, 3H, OCH₃); 3.70 (m, 2H, 2H-6^ꢀ); 4.33 (m, 2H, H-5^ꢀand pyridine

H-4); 4.83 (d, 1H, H-4^ꢀ); 5.05 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.36 (d, J_{1 ,2}= 9.8 Hz, 1H, H-

1^ꢀ); 6.78–7.64 (m, 9H, C₆H₄and C₆H₅); 8.68 (bs, 1H, NH); 9.51 (bs, 1H, NH). Anal.

Calcd. for (C₃₅H₃₇N₃O₁₁S): C, 59.40; H, 5.23; N, 5.94. Found: C, 59.09; H, 5.38; N,

6.03.

ꢀ

5u: yellow, mp: 190°C; yield: (83%); IR.: ν

/Cm⁻¹(KBr) 3375 (NH); 2200

max

(CN); 1752 (CO); ¹H NMR: δ 1.64–2.09 (4s, 12H, 4CH₃CO); 2.44 (s, 3H, CH₃);

H

3.65 (s, 3H, OCH₃); 3.67 (s, 3H, OCH₃); 3.68 (m, 2H, 2H-6^ꢀ); 3.70 (m, 2H, H-

5^ꢀand pyridine H-4); 4.77 (d, 1H, H-4^ꢀ); 5.00 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.36 (d,

J_{1 ,2}= 10.0 Hz, 1H, H-1^ꢀ); 6.80–7.45 (m, 8H, 2C₆H₄); 8.75 (bs, 1H, NH); 9.48 (bs,

1H, NH). Anal. Calcd. for (C₃₆H₃₉N₃O₁₂S): C, 58.61; H, 5.29; N, 5.69. Found: C,

58.86; H, 5.05; N, 5.81.

ꢀ

5v: pale yellow, mp: 185°C; yield: (80%); IR.: ν_max/Cm⁻¹(KBr) 3384 (NH); 2201

(CN); 1752 (CO); 1668 (CO); ¹H NMR: δ 1.93–2.07 (4s, 12H, 4CH₃CO); 2.14 (s,

H

3H, CH₃); 3.65 (s, 3H, OCH₃); 3.69 (m, 2H, 2H-6^ꢀ); 4.34 (m, 2H, H-5^ꢀand pyridine

H-4); 4.84 (d, 1H, H-4^ꢀ); 5.04 (m, 2H, H-3^ꢀand H-2^ꢀ); 5.29 (d, J_{1 ,2}= 9.7 Hz, 1H,

H-1^ꢀ); 6.81–7.64 (m, 8H, 2C₆H₄); 8.86 (bs, 1H, NH); 9.51 (bs, 1H, NH). Anal. Calcd.

for (C₃₅H₃₆ClN₃O₁₁S): C, 56.64; H, 4.85; N, 5.66. Found: C, 56.92; H, 5.13; N, 5.75.

ꢀ

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

11

4-Aryl-3-cyano-6-methyl-2-(2,3,4,6-tetra-O-acetyl-β-D-gluco- and galacto-pyra-

nosylthio)pyridines (7a-v).

General procedures

Method (A). The piperidinium salt of dihydropyridinethiones 3 (0.01 mol) was dis-

solved in dry acetone (5 ml) and a solution of 2,3,4,6-tetra-O-acetyl-α-D-gluco- or

galactopyranosyl bromide (0.01 mol) in dry acetone (20 ml) was then added at 30°C.

The reaction mixture was stirred until the reaction was judged complete by TLC,

using chloroform:petroleum ether 9:1 (Rf, 0.62–0.66), then concentrated under

reduced pressure at 40°C. The resulting product was crystallized from ethanol.

Method (B). A suspension of pyridine thioglycosides 5 (0.01 mol) in ethanol were

reﬂuxed with stirring for 3 min. The resulting products were collected by ﬁltration

and crystallized from ethanol.

Method (C). To a solution of condensed pyridine-2(1H)thiones 9a-p (0.01 mol)

in aqueous potassium hydroxide [0.569, 0.01 mol, in distilled water (6 ml)] was

added a solution of 2,3,4,6-tetra-O-acetyl-α-D-gluco or galacto-pyranosyl bromide

4 (4.521 g, 0.011 mol) in acetone (30 ml). The reaction mixture was stirred at room

temperature until reaction judged to be complete by TLC (30 min to 2 h). The mix-

ture was evaporated under reduced pressure at 40°C and the residue was washed

with distilled water to remove the formed potassium bromide. The product was

dried, and crystallized from ethanol.

Method (D). A mixture of pyridine-2(1H)-thiones 9 (0.01 mol), hexamethyldisi-

lazane (25 ml) and ammonium sulphate (0.02 g) were boiled under reﬂux, with stir-

ring for 48 h. The excess of hexamethyldisilazane was removed under diminished

pressure, providing the silylated bases 11 as a colorless oil. The latter was added to a

solution of 1,2,3,4,6-penta-O-acetyl-α-D-gluco- or galactopyranose (0.011 mol) in

dry acetonitrile (20 ml) and SnCl₄(1.6 ml). The reaction mixture was stirred at room

temperature for (6 h), poured into saturated NaHCO₃solution and then extracted

with CHCl₃. The organic layers were dried over MgSO₄, ﬁltered and then concen-

trated to give the crude nucleosides which were puriﬁed by recrystallization from

ethanol.

7a: pale yellow, mp: 258°C; yield: (72%);¹H NMR: δ 2.00–2.05 (4s, 12H,

H

4CH₃CO); 2.68 (s, 3H, CH₃); 4.06 (m, 3H, 2H-6^ꢀand H-5^ꢀ); 5.06 (t, 1H, H-4^ꢀ); 5.22

(t, 1H, H-3^ꢀ); 5.60 (t, 1H, H-2^ꢀ); 6.22 (d, J_{1 ,2}= 10.1 Hz, 1H, H-1^ꢀ); 7.08–7.48 (m,

10H, 2C₆H₅); 10.43 (bs, 1H, NH). Anal. Calcd. for (C₃₄H₃₃N₃O₁₀S): C, 60.44; H,

4.88; N, 6.22. Found: C, 60.40; H, 4.90; N, 6.05.

ꢀ

7b: pale yellow, mp: 266°C; yield: (76%); IR.: ν_max/Cm⁻¹(KBr) 3449 (NH); 2223

(CN); 1752 (CO); 1650 (CO). Anal. Calcd. for (C₃₅H₃₅N₃O₁₀S): C, 60.95; H, 5.07;

N, 6.09. Found: C, 60.98; H, 5.11; N, 6.01.

12

G. ELGEMEIE AND D. H. EL-NAGGAR

7c: yellow, mp: 232°C; yield: (77%); IR.: ν_max/Cm⁻¹(KBr) 3447 (NH); 2223 (CN);

1752 (CO); 1647 (CO). Anal. Calcd. for (C₃₅H₃₅N₃O₁₁S): C, 59.57; H, 4.96; N, 5.95.

Found: C, 59.42; H, 4.81; N, 5.88.

7d: pale yellow, mp: 261°C; yield: (79%); IR.: ν_max/Cm⁻¹(KBr) 3440 (NH); 2224

(CN); 1751 (CO); 1652 (CO). Anal. Calcd. for (C₃₄H₃₂ClN₃O₁₀S): C, 57.50; H, 4.51;

N, 5.91. Found: C, 57.62; H, 4.49; N, 5.87.

7e: white, mp: 265°C; yield: (75%); IR.: ν_max/Cm⁻¹(KBr) 3472 (NH); 2226 (CN);

1748 (CO); 1650 (CO). Anal. Calcd. for (C₃₅H₃₅N₃O₁₀S): C, 60.95; H, 5.07; N, 6.09.

Found: C, 60.68; H, 5.13; N, 6.25.

7f: pale yellow, mp: 228°C; yield: (73%); IR.: ν_max/Cm⁻¹(KBr) 3464 (NH); 2224

(CN); 1750 (CO); 1649(CO). Anal. Calcd. for (C₃₆H₃₇N₃O₁₀S): C, 61.45; H, 5.26; N,

5.97. Found: C, 61.40; H, 5.38; N, 5.89.

7g: yellow, mp: 176°C; yield: (76%); Anal. Calcd. for (C₃₆H₃₇N₃O₁₁S): C, 60.08;

H, 5.14; N, 5.84. Found: C, 60.27; H, 5.32; N, 5.59.

7h: white, mp: 282°C; yield: (79%); IR.: ν_max/Cm⁻¹(KBr) 3613 (NH); 2227 (CN);

1751 (CO); 1652 (CO). Anal. Calcd. for (C₃₅H₃₄ClN₃O₁₀S): C, 58.05; H, 4.69; N,

5.80. Found: C, 58.50; H, 4.28; N, 5.71.

7i: yellow, mp: 238°C; yield: (78%); IR.: ν_max/Cm⁻¹(KBr) 3289 (NH); 2224 (CN);

1

1749 (CO); 1655 (CO); H NMR: δ 1.99–2.04 (4s, 12H, 4CH₃CO); 2.65 (s, 3H,

H

CH₃); 3.75 (s, 3H, OCH₃); 4.00 (m, 3H, 2H-6^ꢀand H-5^ꢀ); 5.04 (t, 1H, H-4^ꢀ); 5.20 (t,

1H, H-3^ꢀ); 5.59 (t, 1H, H-2^ꢀ); 6.20 (d, J_{1 ,2}= 9.5 Hz, 1H, H-1^ꢀ); 7.01–7.45 (m, 9H,

C₆H₄and C₆H₅); 10.45 (bs, 1H, NH). Anal. Calcd. for (C₃₅H₃₅N₃O₁₁S): C, 59.57;

H, 4.96; N, 5.95. Found: C, 59.48; H, 4.99; N, 5.88.

ꢀ

7j: yellow, mp: 159°C; yield: (74%); IR.: ν_max/Cm⁻¹(KBr) 3419 (NH); 2225 (CN);

1

1750(CO); 1654 (CO); H NMR: δ 1.83–2.16 (4s, 12H, 4CH₃CO); 2.22 (s, 3H,

H

CH₃); 2.65 (s, 3H, CH₃); 3.76 (s, 3H, OCH₃); 4.01 (m, 3H, 2H-6^ꢀand H-5^ꢀ); 5.01 (t,

1H, H-4^ꢀ); 5.17 (t, 1H, H-3^ꢀ); 5.54 (t, 1H, H-2^ꢀ); 6.19 (d, J_{1 ,2}= 10.8 Hz, 1H, H-1^ꢀ);

ꢀ

7.00–7.45 (m, 8H, 2C₆H₄); 10.30 (bs, 1H, NH);¹³C NMR: δ 20.3–20.4 (4CH₃CO);

C

22.8 (CH₃); 30.6 (CH₃); 55.2 (OCH₃); 61.8 (C-6^ꢀ); 68.1 (C-4^ꢀ); 68.8 (C-2^ꢀ); 73.2 (C-

3^ꢀ); 75.1 (C-5^ꢀ); 80.2 (C-1^ꢀ); 104.9 (C-3); 113.9 (CN); 114.7–135.0 (2Ar-C); 151.2 (C-

5); 157.9 (C-4); 158.5 (C-6); 160.2 (C-2); 163.5–169.9 (4CO of glucose); 182.3 (CO

of pyridine). Anal. Calcd. for (C₃₆H₃₇N₃O₁₁S): C, 60.08; H, 5.14; N, 5.84. Found: C,

60.35; H, 5.08; N, 5.88.

7k: yellow, mp: 267°C; yield: (72%); IR.: ν

/Cm⁻¹(KBr) 3444 (NH); 2223

max

1

(CN); 1751 (CO); 1648 (CO); H NMR: δ 1.98–2.08 (4s, 12H, 4CH₃CO); 2.64

H

(s, 3H, CH₃); 3.69 (s, 3H, OCH₃); 3.76 (s, 3H, OCH₃); 3.99 (m, 3H, 2H-6^ꢀand H-

5^ꢀ); 5.00 (t, 1H, H-4^ꢀ); 5.16 (t, 1H, H-3^ꢀ); 5.54 (t, 1H, H-2^ꢀ); 6.19 (d, J_{1 ,2}= 9.8 Hz,

ꢀ

1H, H-1^ꢀ); 6.86–7.45 (m, 8H, 2C₆H₄); 10.25 (bs, 1H, NH);¹³C NMR: δ 20.3–20.4

C

(4CH₃CO); 22.8 (CH₃); 55.2 (OCH₃); 61.8 (C-6^ꢀ); 68.1 (C-4^ꢀ); 68.8 (C-2^ꢀ); 73.1 (C-

3^ꢀ); 75.0 (C-5^ꢀ); 80.2 (C-1^ꢀ); 104.9 (C-3); 114.7 (CN); 121.4–157.8 (2Ar-C); 158.0 (C-

5); 160.3 (C-4); 160.3 (C-6); 163.3 (C-2); 169.3–169.9 (4CO of glucose); 179.8 (CO

of pyridine). Anal. Calcd. for (C₃₆H₃₇N₃O₁₂S): C, 58.77; H, 5.03; N, 5.71. Found: C,

58.89; H, 5.24; N, 5.59.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

13

7l: yellow, mp: 298°C; yield: (73%); IR.: ν_max/Cm⁻¹(KBr) 3438 (NH); 2226 (CN);

1

1752 (CO); 1650 (CO); H NMR: δ 1.98–2.13 (4s, 12H, 4CH₃CO); 2.56 (s, 3H,

H

CH₃); 3.76 (s, 3H, OCH₃); 4.00 (m, 3H, 2H-6^ꢀand H-5^ꢀ); 5.00 (t, 1H, H-4^ꢀ); 5.08

(t, 1H, H-3^ꢀ); 5.19 (t, 1H, H-2^ꢀ); 6.02 (d, J_{1 ,2}= 10.6 Hz, 1H, H-1^ꢀ); 6.96–7.44 (m,

ꢀ

8H, 2Ar-H); 10.50 (bs, 1H, NH);¹³C NMR: δ 20.3–20.4 (4CH₃CO); 22.8 (CH₃);

C

55.1 (OCH₃); 61.7 (C-6^ꢀ); 68.0 (C-4^ꢀ); 68.7 (C-2^ꢀ); 73.2 (C-3^ꢀ); 75.1 (C-5^ꢀ); 80.2 (C-

1^ꢀ); 104.8 (C-3); 114.5 (CN); 121.0–158.4 (2Ar-C); 160.2 (C-5); 160.3 (C-4); 162.5

(C-6); 163.9 (C-2); 169.1–169.8 (4CO of glucose); 178.1 (CO of pyridine). Anal.

Calcd. for (C₃₅H₃₄ClN₃O₁₁S): C, 56.79; H, 4.59; N, 5.67. Found: C, 56.56; H, 4.68;

N, 5.75.

7m: white, mp: 280°C; yield: (77%); IR.: ν

/Cm⁻¹(KBr) 3465 (NH); 2225

max

(CN); 1750 (CO); 1649 (CO); ¹³C NMR: δ 20.3–20.4 (4CH₃CO); 22.8 (CH₃);

C

61.8 (C-6^ꢀ); 68.0 (C-4^ꢀ); 68.8 (C-2^ꢀ); 73.1 (C-3^ꢀ); 75.0 (C-5^ꢀ); 80.2 (C-1^ꢀ); 104.7 (C-

3); 114.3 (CN); 119.7–137.9 (2Ar-C); 150.2 (C-5); 158.0 (C-4); 158.7 (C-6); 163.3

(C-2); 169.0–170.0 (4CO of glucose); 181.2 (CO of pyridine). Anal. Calcd. for

(C₃₄H₃₂ClN₃O₁₀S): C, 57.50; H, 4.51; N, 5.91. Found: C, 57.59; H, 4.77; N, 5.62.

7n: yellow, mp: 251°C; yield: (78%); IR.: ν

/Cm⁻¹(KBr) 3452 (NH); 2220

max

(CN); 1750 (CO); 1648 (CO); ¹³C NMR: δ 25.6–25.7 (4CH₃CO); 28.1 (CH₃); 67.0

C

(C-6^ꢀ); 73.34 (C-4^ꢀ); 74.10 (C-2^ꢀ); 78.3 (C-3^ꢀ); 80.3 (C-5^ꢀ); 85.49 (C-1^ꢀ); 110.0 (C-

3); 119.6 (CN); 124.9–140.6 (2Ar-C); 155.4 (C-5); 163.2 (C-4); 164.0 (C-6); 168.3

(C-2); 174.3–175.0 (4CO of glucose); 182.5 (CO of pyridine). Anal. Calcd. for

(C₃₅H₃₄ClN₃O₁₀S): C, 58.05; H, 4.69; N, 5.80. Found: C, 58.43; H, 4.52; N, 5.86.

7o: yellow, mp: 209°C; yield: (74%); IR.: ν

/Cm⁻¹(KBr) 3440 (NH); 2225

max

(CN); 1751 (CO); 1644 (CO);¹H NMR: δ 1.99–2.03 (4s, 12H, 4CH₃CO); 2.66 (s,

H

3H, CH₃); 3.69 (s, 3H, OCH₃); 3.99 (m, 3H, 2H-6^ꢀand H-5^ꢀ); 5.00 (t, 1H, H-4^ꢀ); 5.16

(t, 1H, H-3^ꢀ); 5.55 (t, 1H, H-2^ꢀ); 6.20 (d, J_{1 ,2}= 10.2 Hz, 1H, H-1 ); 6.83–7.59 (m, 8H,

ꢀ

2C₆H₄); 10.31 (bs, 1H, NH);¹³C NMR: δ 20.3–20.4 (4CH₃CO); 22.8 (CH₃); 55.2

C

(OCH₃); 61.8 (C-6^ꢀ); 68.0 (C-4^ꢀ); 68.8 (C-2^ꢀ); 73.1 (C-3^ꢀ); 75.0 (C-5^ꢀ); 80.2 (C-1^ꢀ);

104.7 (C-3); 114.0 (CN); 114.4–150.2 (2Ar-C); 156.0 (C-5); 157.0 (C-4); 158.9 (C-

6); 162.9 (C-2); 169.3–170.0 (4CO of glucose); 181.5 (CO of pyridine). Anal. Calcd.

for (C₃₅H₃₄ClN₃O₁₁S): C, 56.79; H, 4.59; N, 5.67. Found: C, 56.85; H, 4.49; N, 5.71.

7p: yellow, mp: 235°C; yield: (76%); IR.: ν

/Cm⁻¹(KBr) 3450 (NH); 2226

max

(CN); 1751 (CO); 1648 (CO); ¹³C NMR: δ 20.3–20.4 (4CH₃CO); 22.8 (CH₃);

C

61.7 (C-6^ꢀ); 68.0 (C-4^ꢀ); 68.8 (C-2^ꢀ); 73.1 (C-3^ꢀ); 75.0 (C-5^ꢀ); 80.2 (C-1^ꢀ); 104.3 (C-

3); 114.5 (CN); 121.1–136.8 (2Ar-C); 151 (C-5); 157.5 (C-4); 158.7 (C-6); 163.1

(C-2); 169.3–170.0 (4CO of glucose); 180.3 (CO of pyridine). Anal. Calcd. for

(C₃₄H₃₁Cl₂N₃O₁₀S): C, 54.83; H, 4.16; N, 5.64. Found: C, 55.09; H, 4.21; N, 5.32.

7q: yellow, mp: 206°C; yield: (72%); IR.: ν

/Cm⁻¹(KBr) 3459 (NH); 2225

max

(CN); 1751 (CO); 1646 (CO). Anal. Calcd. for (C₃₄H₃₃N₃O₁₀S): C, 60.44; H, 4.88;

N, 6.22. Found: C, 60.41; H, 4.50; N, 5.40.

7r: white, mp: 191°C; yield: (72%); IR.: ν_max/Cm⁻¹(KBr) 3475 (NH); 2224 (CN);

1752 (CO); 1645 (CO). Anal. Calcd. for (C₃₆H₃₇N₃O₁₀S): C, 61.45; H, 5.26; N, 5.97.

Found: C, 61.09; H, 5.53; N, 5.99.

14

G. ELGEMEIE AND D. H. EL-NAGGAR

7s: yellow, mp: 186°C; yield: (78%); IR.: ν_max/Cm⁻¹(KBr) 3441 (NH); 2222 (CN);

1751 (CO); 1650 (CO). Anal. Calcd. for (C₃₆H₃₇N₃O₁₁S): C, 60.08; H, 5.14; N, 5.84.

Found: C, 60.01; H, 5.35; N, 5.78.

7t: white, mp: 262°C; yield: (79%); IR.: ν_max/Cm⁻¹(KBr) 3390 (NH); 2201 (CN);

1752 (CO); 1668 (CO). Anal. Calcd. for (C₃₅H₃₅N₃O₁₁S): C, 59.57; H, 4.96; N, 5.95.

Found: C, 59.46; H, 4.87; N, 5.99.

7u: pale yellow, mp: 230°C; yield: (78%); IR.: ν_max/Cm⁻¹(KBr) 3382 (NH); 2200

(CN); 1752 (CO); 1669 (CO). Anal. Calcd. for (C₃₆H₃₇N₃O₁₂S): C, 58.77; H, 5.03;

N, 5.71. Found: C, 58.79; H, 5.42; N, 5.62.

7v: yellow, mp: 203°C; yield: (79%); IR.: ν

/Cm⁻¹(KBr) 3474 (NH); 2201

max

(CN); 1752 (CO); 1669 (CO). Anal. Calcd. for (C₃₅H₃₄ClN₃O₁₁S): C, 56.79; H, 4.59;

N, 5.67. Found: C, 56.82; H, 4.57; N, 5.56.

4-Aryl-3-cyano-6-methyl-2-(β-D-gluco- and galactopyranosylthio)-pyridines

(8a-v).

General procedures

Dry gaseous ammonia was passed through a solution of protected nucleoside

7 (0.5 g) in dry methanol (20 ml) at room temperature for 10 min. The mix-

ture was stirred until the reaction was judged complete by TLC (10–12h) using

CHCl3:MeOH, 9:1 (Rf, 0.66–0.68). The resulting mixture was then concen-

trated under reduced pressure to aﬀord a solid residue that was crystallized from

methanol.

8a: pale yellow, mp: 282°C; yield: (60%). Anal. Calcd. for (C₂₆H₂₅N₃O₆S): C,

61.53; H, 4.93; N, 8.28. Found: C, 62.01; H, 4.42; N, 8.39.

8b: pale yellow, mp: 346°C; yield: (58%). Anal. Calcd. for (C₂₇H₂₇N₃O₆S): C,

62.18; H, 5.18; N, 8.06. Found: C, 62.53; H, 5.11; N, 8.26.

8c: yellow, mp: 282°C; yield: (62%). Anal. Calcd. for (C₂₇H₂₇N₃O₇S): C, 60.33; H,

5.02; N, 7.82. Found: C, 60.75; H, 5.29; N, 7.34.

8d: white, mp: 290°C; yield: (60%). Anal. Calcd. (C₂₆H₂₄ClN₃O₆S): C, 57.61; H,

4.43; N, 7.75. Found: C, 57.29; H, 4.67; N, 7.93.

8e: white, mp: 224°C; yield: (61%); ¹H NMR: δ 2.28 (s, 3H, CH₃); 2.60 (s, 3H,

H

CH₃); 3.17–3.66 (m, 6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 4.47 (t, 2H, 2^ꢀ-OH and

3^ꢀ-OH); 5.05 (d,1H, 4^ꢀ-OH); 5.23 (d,1H, 6^ꢀ-OH); 5.58 (d, J_{1 ,2}= 9.8 Hz, 1H, H-1^ꢀ);

7.04–7.59 (m, 9H, C₆H₄and C₆H₅); 10.57 (bs, 1H, NH);¹³C NMR: δ 19.5 (CH₃);

21.7 (CH₃); 59.4 (C-6^ꢀ); 68.4 (C-4^ꢀ); 70.4 (C-2^ꢀ); 77.3 (C-3^ꢀ); 80.4 (C-5^ꢀ^C); 82.3 (C-1^ꢀ);

103.1 (C-3); 113.6 (CN); 118.4–138.0 (2Ar-C); 150.0 (C-5); 157.0 (C-4); 159.1 (C-6);

162.6 (C-2); 178.0 (CO). Anal. Calcd. for (C₂₇H₂₇N₃O₆S): C, 62.18; H, 5.18; N, 8.06.

Found: C, 62.46; H, 5.53; N, 8.27.

ꢀ

8f: white, mp: 217°C; yield: (59%); ¹H NMR: δ 2.22 (s, 3H, CH₃); 2.29 (s, 3H,

H

CH₃); 2.58 (s, 3H, CH₃); 3.21–3.48 (m, 6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ);

4.45 (t, 2H, 2^ꢀ-OH and 3^ꢀ-OH); 5.03 (d,1H, 4^ꢀ-OH); 5.22 (d,1H, 6^ꢀ-OH); 5.56 (d,

J_{1 ,2}= 10.0 Hz, 1H, H-1^ꢀ); 7.06–8.44 (m, 8H, 2C₆H₄); 10.26 (bs, 1H, NH);¹³C

ꢀ

NMR: δ 20.7 (CH₃); 21.1 (CH₃); 23.3 (CH₃); 61.0 (C-6^ꢀ); 70.0 (C-4^ꢀ); 72.0

C

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

15

(C-2^ꢀ); 78.9 (C-3^ꢀ); 82.0 (C-5^ꢀ); 83.9 (C-1^ꢀ); 104.7 (C-3); 115.2 (CN); 120.0–139.6

(2Ar-C); 155.5 (C-5); 158.6 (C-4); 160.6 (C-6); 164.0 (C-2); 179.1 (CO). Anal. Calcd.

for (C₂₈H₂₉N₃O₆S): C, 62.80; H, 5.42; N, 7.85. Found: C, 62.37; H, 5.83; N, 7.52.

1

8g: pale yellow, mp: 230°C; yield: (60%); H NMR: δ 1.77 (s, 3H, CH₃); 2.33

H

(s, 3H, CH₃); 3.23–3.26 (m, 6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 3.71 (s, 3H,

OCH₃); 4.47 (t, 2H, 2^ꢀ-OH and 3^ꢀ-OH); 5.03 (d,1H, 4^ꢀ-OH); 5.22 (d,1H, 6^ꢀ-OH);

ꢀ

13

ꢀ

5.56 (d, J_{1 ,2}= 9.9 Hz, 1H, H-1 ); 6.83–7.40 (m, 8H, 2C₆H₄); 10.29 (bs, 1H, NH); C

NMR: δ 21.4 (CH₃); 23.5 (CH₃); 55.7 (OCH₃); 61.3 (C-6^ꢀ); 70.2 (C-4^ꢀ); 72.3 (C-

C

2^ꢀ); 79.1 (C-3^ꢀ); 82.3 (C-5^ꢀ); 84.2 (C-1^ꢀ); 104.9 (C-3); 114.5 (CN); 115.5–151.8 (2Ar-

C); 156.5 (C-5); 158.8 (C-4); 160.8 (C-6); 164.0 (C-2); 172.1 (CO). Anal. Calcd. for

(C₂₈H₂₉N₃O₇S): C, 60.98; H, 5.26; N, 7.62.

Found: C, 61.20; H, 5.47; N, 7.21.

8h: yellow, mp: 259°C; yield: (61%). Anal. Calcd. for (C₂₇H₂₆ClN₃O₆S): C, 58.32;

H, 4.68; N, 7.56. Found: C, 58.73; H, 4.32; N, 7.75.

8i: yellow, mp: 272°C; yield: (59%). Anal. Calcd. for (C₂₇H₂₇N₃O₇S): C, 60.33; H,

5.02; N, 7.82. Found: C, 60.64; H, 5.50; N, 7.47.

8j: yellow, mp: 214°C; yield: (60%); ¹H NMR: δ 2.23 (s, 3H, CH₃); 2.59 (s, 3H,

H

CH₃); 3.26–3.43 (m, 6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 3.76 (s, 3H, OCH₃); 4.52

(t, 2H, 2^ꢀ-OH and 3^ꢀ-OH); 5.10 (d,1H, 4^ꢀ-OH); 5.29 (d,1H, 6^ꢀ-OH); 5.62 (d, J_{1 ,2}

=

ꢀ

10.3 Hz, 1H, H-1^ꢀ); 7.01–7.45 (m, 8H, 2C₆H₄); 10.38 (bs, 1H, NH);¹³C NMR: δ 18.7

C

(CH₃); 21.2 (CH₃); 53.5 (OCH₃); 59.0 (C-6^ꢀ); 68.0 (C-4^ꢀ); 70.0 (C-2^ꢀ); 76.8 (C-3^ꢀ);

80.0 (C-5^ꢀ); 81.9 (C-1^ꢀ); 102.7 (C-3); 112.0 (CN); 117.9–149.3 (2Ar-C); 156.5 (C-5);

158.4 (C-4); 158.6 (C-6); 162.1 (C-2); 173.0 (CO). Anal. Calcd. for (C₂₈H₂₉N₃O₇S):

C, 60.98; H, 5.26; N, 7.62.

Found: C, 61.22; H, 5.43; N, 7.18.

8k: yellow, mp: 236°C; yield: (61%); ¹H NMR: δ 2.08 (s, 3H, CH₃); 3.21–3.66 (m,

H

6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 3.76 (s, 3H, OCH₃); 3.83 (s,3H, OCH₃); 4.45

(t, 2H, 2^ꢀ-OH and 3^ꢀ-OH); 5.04 (d,1H, 4^ꢀ-OH); 5.22 (d,1H, 6^ꢀ-OH); 5.57 (d, J_{1 ,2}

=

ꢀ

10.7 Hz, 1H, H-1^ꢀ); 6.83–7.43 (m, 8H, 2C₆H₄); 10.26 (bs, 1H, NH);¹³C NMR: δ 22.0

C

(CH₃); 54.2 (OCH₃); 54.3 (OCH₃); 59.8 (C-6^ꢀ); 68.7 (C-4^ꢀ); 70.8 (C-2^ꢀ); 77.6 (C-3^ꢀ);

80.7 (C-5^ꢀ); 82.6 (C-1^ꢀ); 103.5 (C-3); 114.1 (CN); 120.4–150.1 (2Ar-C); 155.0 (C-5);

157.3 (C-4); 159.2 (C-6); 162.6 (C-2); 175.0 (CO). Anal. Calcd. for (C₂₈H₂₉N₃O₈S):

C, 59.25; H, 5.11; N, 7.40.

Found: C, 59.32; H, 5.45; N, 7.49.

1

8l: yellow, mp: 195°C; yield: (62%); H NMR: δ 2.08 (s, 3H, CH₃); 3.25–

H

3.47 (m, 6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 3.75 (s, 3H, OCH₃); 4.44 (t,

2H, 2^ꢀ-OH and 3^ꢀ-OH); 5.03 (d,1H, 4^ꢀ-OH); 5.21 (d,1H, 6^ꢀ-OH); 5.56 (d, J_{1 ,2}

=

ꢀ

9.7 Hz, 1H, H-1^ꢀ); 7.00–8.61 (m, 8H, 2C₆H₄); 10.66 (bs, 1H, NH). Anal. Calcd.

for (C₂₇H₂₆ClN₃O₇S): C, 56.69; H, 4.54; N, 7.34. Found: C, 56.33; H, 4.34; N,

7.53.

1

8m: white, mp: 211°C; yield: (60%); H NMR: δ 2.61 (s, 3H, CH₃); 3.21–

H

3.48 (m, 6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 4.46 (t, 2H, 2^ꢀ-OH and 3^ꢀ-

OH); 5.04 (d,1H, 4^ꢀ-OH); 5.23 (d,1H, 6^ꢀ-OH); 5.62 (d, J_{1 ,2}= 10.1 Hz, 1H,

ꢀ

H-1^ꢀ); 7.05–8.60 (m, 9H, C₆H₄and C₆H₅); 10.40 (bs, 1H, NH). Anal. Calcd.

16

G. ELGEMEIE AND D. H. EL-NAGGAR

for (C₂₆H₂₄ClN₃O₆S): C, 57.61; H, 4.43; N, 7.75. Found: C, 58.01; H, 4.75; N,

7.51.

8n: pale yellow, mp: 215°C; yield: (61%). Anal. Calcd. for (C₂₇H₂₆ClN₃O₆S): C,

58.32; H, 4.68; N, 7.56. Found: C, 58.59; H, 4.83; N, 7.51.

8o: yellow, mp: 298°C; yield: (60%). Anal. Calcd. for (C₂₇H₂₆ClN₃O₇S): C, 56.69;

H, 4.54; N, 7.34. Found: C, 56.32; H, 4.76; N, 7.65.

8p: yellow, mp: 217°C; yield: (60%); ¹H NMR: δ 2.60 (s, 3H, CH₃); 3.20–3.66 (m,

H

6H, 2H-6^ꢀ, H-5^ꢀ, H-4^ꢀ, H-3^ꢀand H-2^ꢀ); 4.44 (t, 2H, 2^ꢀ-OH and 3^ꢀ-OH); 5.03 (d,1H,

4^ꢀ-OH); 5.22 (d,1H, 6^ꢀ-OH); 5.57 (d, J_{1 ,2}= 9.7 Hz, 1H, H-1^ꢀ); 7.30–8.61 (m, 8H,

2C₆H₄); 10.61 (bs, 1H, NH). Anal. Calcd. for (C₂₆H₂₃Cl₂N₃O₆S): C, 54.16; H, 3.99;

N, 7.29. Found: C, 54.55; H, 4.09; N, 7.35.

ꢀ

8q: yellow, mp: 212°C; yield: (59%). Anal. Calcd. for (C₂₆H₂₅N₃O₆S): C, 61.53;

H, 4.93; N, 8.28. Found: C, 62.01; H, 4.86; N, 8.47.

8r: white, mp: 288°C; yield: (60%). Anal. Calcd. for (C₂₈H₂₉N₃O₆S): C, 62.80; H,

5.42; N, 7.85. Found: C, 63.11; H, 5.21; N, 7.97.

8s: yellow, mp: 284°C; yield: (61%). Anal. Calcd. for (C₂₈H₂₉N₃O₇S): C, 60.98; H,

5.26; N, 7.62. Found: C, 60.87; H, 5.19; N, 7.83.

8t: yellow, mp: 256°C; yield: (59%). Anal. Calcd. for (C₂₇H₂₇N₃O₇S): C, 60.33; H,

5.02; N, 7.82. Found: C, 60.31; H, 5.45; N, 7.91.

8u: white, mp: 283°C; yield: (60%). Anal. Calcd. for (C₂₈H₂₉N₃O₈S): C, 59.25; H,

5.11; N, 7.40. Found: C, 59.32; H, 5.09; N, 7.57.

8v: pale yellow, mp: 240°C; yield: (61%). Anal. Calcd. for (C₂₇H₂₆ClN₃O₇S): C,

56.69; H, 4.54; N, 7.34. Found: C, 56.74; H, 4.42; N, 7.57.

4-Aryl-3-cyano-6-methyl-2-(methylthio)-1,4-dihydropyridines (12a,b)

General procedures

A mixture of 1 (0.01 mol) and 2 (0.01 mol) was dissolved in dry ethanol (5 ml),

and then piperidine (0.01 mol) was added. The reaction mixture was stirred at

0°C for 1 h and then left to stand to room temperature. The solvent was removed

at reduced pressure and the resulting piperidinium salt of 1,4-dihydropyridine-2-

thione (3) was dissolved in dry acetone (5 ml) and a solution of methyl iodide

(0.015 mol) in dry acetone (20 ml) was then added at 0°C. The reaction mixture

was stirred until the reaction was judged complete by TLC, then concentrated under

reduced pressure and the residue crystallized from chloroform-petroleum ether at

0°C.

12a: pale yellow, mp: 165°C; yield: (80%); IR.: ν

/Cm⁻¹(KBr) 3262 (NH);

max

2197 (CN); 1632 (CO). Anal. Calcd. for (C₂₂H₂₁N₃OS): C, 70.40; H, 5.60; N, 11.20.

Found: C, 70.62; H, 5.41; N, 11.08.

12b: pale yellow, mp: 125°C; yield: (83%); IR.: ν

/Cm⁻¹(KBr) 3438 (NH);

max

2195 (CN); 1644 (CO); ¹H NMR: δ 2.09 (s, 3H, CH₃); 3.38 (s, 3H, CH₃); 4.78 (s,

H

1H, pyridine H-4); 6.98-7.56 (m, 9H, C₆H₄and C₆H₅); 9.10 (bs, 1H, NH); 9.71 (bs,

1H, NH). Anal. Calcd. for (C₂₁H₁₈ClN₃OS): C, 63.71; H, 4.55; N, 10.60. Found: C,

63.95; H, 4.79; N, 10.81.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS

17

4-Aryl-3-cyano-6-methyl-2-(methylthio)-pyridines (10a,b)

General procedures

Method (A). The piperidinium salt of dihydro-pyridinethiones 3 (0.01 mol) was

dissolved in dry acetone (5 ml) and a solution of methyl iodide (0.015 mol) in dry

acetone (20 ml) was then added at 30°C. The reaction mixture was stirred until the

reaction was judged complete by TLC, then evaporated under reduced pressure at

40°C and the resulting product was crystallized from ethanol.

Method (B). pyridine-2(1H)thiones 9 (0.01 mole) was stirred with methyl idodie

(0.015 mol) and potassium hydroxide (0.01 mol) in dichloromethame (30 ml) for

6 hours. The resulting product was collected by ﬁltration and puriﬁed by recrystal-

lization from ethanol.

10a: pale yellow, mp: 233°C; yield: (79%); IR.: ν

/Cm⁻¹(KBr) 3439 (NH);

max

1

2222 (CN); 1642 (CO); H NMR: δ 2.06 (s, 3H, CH₃); 2.40 (s, 3H, CH₃); 2.60

H

(s, 3H, SCH₃); 7.08-8.0 (m, 9H, C₆H₅and C₆H₄); 10.44 (bs, 1H, NH); ¹³C NMR:

δ 16.00 (CH₃); 20.00 (CH₃); 30.5 (SCH₃); 104.0 (C3); 110.0 (CN); 121.3–129.0

C

(2Ar-C); 130 (C-5); 146 (C-4); 150.0 (C6); 168.0 (C2); 177.0 (CO). Anal. Calcd.

for (C₂₂H₁₉N₃OS): C, 70.47; H, 5.69; N, 11.26. Found: C, 70.85; H, 5.71; N,

11.01.

10b: pale yellow, mp: 273°C; yield: (78%); IR.: ν

/Cm⁻¹(KBr) 3435 (NH);

max

2220 (CN); 1648 (CO); ¹H NMR: δ 2.50 (s, 3H, CH₃); 2.69 (s, 3H, CH₃); 7.08–7.60

H

(m, 9H, C₆H₄and C₆H₅); 10.44 (bs, 1H, NH). Anal. Calcd. for (C₂₁H₁₆ClN₃OS): C,

64.04; H, 4.06; N, 10.67. Found: C, 64.37; H, 4.31; N, 10.77.

Anti proliferative activity

Cells were plated in 96-multiwell plate (104 cells /well) for 24 hr before treatment

with the compounds to allow attachment of cell to the wall of plate. For each tested

compound, a solution of the compound was prepared by dissolving 1µM of each in

dimethyl sulfoxide. After being incubated for 24 hr, cells were treated with diﬀerent

concentrations of each compound under test (0, 25, 50 and 100 µM) were added to

the cell monolayer octet wells were prepared for each individual dose. Monolayer

cells were incubated with the compound(s) for 48 h at 37°C and in atmosphere

of 5% CO₂. Control cells were treated with vehicle alone. After 48 hr, cells were

ﬁxed, washed and stained with MTT Stain (1.2 mM) dissolved in 1% hydrochloric

acid for 2 hr. Excess stain was washed with sodium dodecyl sulfate in hydrochlo-

ric acid. Color intensity was measured in an ELISA reader at wave length of

550 nm.

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Article Doi

Novel dihydropyridine thioglycosides and their corresponding dehydrogenated forms as potent anti-hepatocellular carcinoma agents

DOI: 10.1080/15257770.2018.1457161

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