Synthesis and anticancer activity of N-9- and N-7- substituted 1,2,3 triazole analogues of 2,6-di-substituted purine

MEDICINAL

CHEMISTRY

RESEARCH

Medicinal Chemistry Research

https://doi.org/10.1007/s00044-019-02456-9

ORIGINAL RESEARCH

Synthesis and anticancer activity of N-9- and N-7- substituted 1,2,3

triazole analogues of 2,6-di-substituted purine

Jabeena Khazir¹Bilal Ahmad Mir²Gousia Chashoo³Lynne Pilcher⁴Darren Riley⁴

●

Received: 27 June 2019 / Accepted: 5 October 2019

Abstract

A library of N-9- and N-7-substituted 1,2,3 triazole analogues were generated on the 2,6-di-substituted purine upon reaction

with various substituted aromatic azides. The synthesised analogues were screened for in vitro cytotoxic activity against

various human cancer cell lines like (HCT-1 (colon), THP-1 (leukaemia), IMR-32 (neuroblastoma) and A-549 (lung)). From

the bioassay results, it was observed that even though most of the synthesized derivatives exhibited a good potency against

various screened cancer cell lines, but few of the analogues like 9a, 9b and 9e were found to be the most potent analogues in

the series, with compound 9a showing IC₅₀values of 0.08 and 0.4 μM against THP-1 and A-549 cell lines, respectively.

●

Keywords 2,6 Dichloropurine Cycloaddition 1,2,3 triazoles anticancer

Abbreviations

Introduction

Ph

Phenyl ring

Ba

T

Pu

Ea

Py

Pi

CH2Ba

Benzyl amine

Triazole ring

Purine ring

Ethanol amine

Pyrolidine

Piperidine

Methylene group attached to benzene ring of

benzyl amine

Methylene group attached to Triazole ring

Purine structural framework (7H-Pyrrolo[2,3-d]pyrimidine)

is the heterocyclic compound, which is most commonly

found in nature and is often found in several molecules with

proven biological properties (Jeannette et al. 2015). This

heterocyclic structure as such is not known in nature, but

exists in the form of substituted purines like adenine and

guanine or their derivatives, which play essential roles in a

broad variety of functions in living species (Rosemeyer

2004; Legraverend and Grierson 2006). Therefore, this

heterocyclic structure received the title of ‘privileged scaf-

fold’ a phrase that has been used in the analysis of multiple

molecules of the same scaffold with the same activity

(Welsch et al. 2010). The screening of purine analogues

against an ample range of biological targets has led to the

opening of its new applications as therapeutic agents and

has been found effective as chemotherapeutics (antiviral,

antibiotic and anticancer agents) (De Clercq 1997; Melroy

and Nair 2005; Kay 1981; Nabhan et al. 2004; Marr 1991;

Panos et al. 1996; Quan and Peters 2004). They exert their

chemotherapeutic property by causing inhibition or acting

as substrates of enzymes involved in metabolism of purine

like adenosine deaminase, guanase, hypoxanthine-guanine

phosphoribosyltransferase (HGPRT), polynucleotide phos-

phorylase (PNPase), etc. 6-Mercaptopurine, thioguanine are

some of the examples of anticancer drugs containing a

purine structural framework, and acyclovir, ganciclovir,

carbovir, abacavir are few examples of purine-based drugs

acting as antiviral agents against herpes or AIDS (Hansen

CH2T

Supplementary information The online version of this article (https://

doi.org/10.1007/s00044-019-02456-9) contains supplementary

material, which is available to authorised users.

* Jabeena Khazir

jabina.khazir@gmail.com

1

Department of Chemistry, Government Degree College (Boys),

Pulwama, Jammu and Kashmir, India

2

Department of Botany, Satellite Campus Kargil, University of

Kashmir, Srinagar, Jammu and Kashmir, India

3

Cancer Pharmacology Division, CSIR-Indian Institute of

Integrative Medicine, Canal Road, Jammu 180001, India

4

Department of Chemistry, University of Pretoria, Pretoria 0028,

South Africa

Medicinal Chemistry Research

Cl

Fig. 1 Structures of some 2,6,

9-subtituted purines showing

anticancer property

NH

N

H

N

H

N

H

OH

(R)-roscovitine (1)

Olomoucine (2)

Purvanalol-A (3)

et al. 1985; Munshi et al. 2014; Masson 1983; Wang et al.

2015; Vince 1991). Various substituted purine analogues

have been synthesised and screened for their cytotoxic

activity over the last decades. Early discoveries of various

CDK inhibitors like roscovitine 1, olomoucine 2, purvanalol

3 (Fig. 1), and many other compounds related to them were

obtained from the systematic modiﬁcation of purine skeleton

(Havlicek et al. 1997; McClue et al. 2002; MacCallum et al.

2005; Whittaker et al. 2007; Hsieh et al. 2009). Some other

purine derivatives like myoseverin are microtubule assembly

inhibitors, leading to cytostatic activity by inducing apoptosis

(Perez et al. 2002). Most of the purine analogues, which

exhibit potent anticancer activity, have been observed to

contain a aromatic moiety, such as benzylamine at position 6

that has been found to bind to the hydrophobic pocket near

the active site of CDKs (Mary et al. 2015). R-enantiomer of

CDK inhibitor (roscovitine) is in clinical trials against cancer

in patients diagnosed with non-small lung cancer, or other

malignancies (Siegel-Lakhai et al. 2005).

Taking into consideration the toxic side effects of the

current convectional chemotherapeutic agents, searching and

developing new chemical entities with special characteristics

as effective anticancer molecules have been an important

driving force for the development of novel anticancer agents,

wherein the drug should show cytotoxic effect only on cancer

cells without affecting the normal cells (Saman et al. 2018).

Therefore, keeping in view the anticancer potential of

purine scaffold and searching for more potent anticancer

analogues from purine scaffold, herein we report the synth-

esis and cytotoxic evaluation of N-9- and N-7-substituted

1,2,3 triazole analogues of 2,6-di-substituted purine.

propargyle bromide as alkylating agent, potassium carbo-

nate as base and acetone as solvent at room temperature

resulting in a mixture of alkylated purines regioisomers (5

and 6) at position N-9 and N-7. N-7-alkylated regioisomer

was obtained in minor yield whose structure besides

spectral analysis was also conﬁrmed by X-Ray crystal

structure (Fig. 2). The SNAr on C6 position was efﬁciently

achieved with complete regiospeciﬁty using primary amine

nucleophiles like benzylamine and aminoethanol,1-butanol

as solvent and disopropylethylamine as base followed by

reﬂuxing for 12 h to form the compound 7 and compound

10, which were, respectively, allowed to undergo 3 + 2

cycloaddition with variously substituted aromatic azides to

form N-9- and N-7-substituted 1,2,3 triazoles 8(a–x) and 11

(a–x) on the purine scaffold. Finally, the SNAr on C2 of

each synthesised analogue was achieved using the cyclic

secondary amine bases like pyrolidine and piperidine in the

presence of 1-butanol as solvent followed by reﬂuxing for

12 h to form the required compounds 9(a–x) and 12(a–h).

1

All the compounds were identiﬁed by HNMR, ¹³C, MS

and further veriﬁed by X-ray crystal structure. Figure 3

represents the X-ray crystallographic structure of com-

pound 9g.

Biological activity

In vitro anticancer activity of the N-9-substituted 1,2,3

triazole analogues of 2,6-di-substituted purine

N-9-substituted 1,2,3 triazole analogues of 2,6-di-sub-

stituted purine (9a–9x) were evaluated for in vitro antic-

ancer activity against a panel of four human cancer cell

lines, such as HCT-1 (colon), THP-1 (leukaemia), IMR-32

(neuroblastoma) and A-549 (lung). Table 3 summarises the

inhibitory activity (IC₅₀) values of the analogues synthe-

sised and the well-known purine-derived anticancer drug

5-ﬂuorouracil, which was used as standard drug. From the

results of screening, it was observed that some of the N-9-

substituted 1,2,3 triazole analogues showed very potent

anticancer activities in lower μM range against all the

Results and discussion

Chemistry

2,6,9- and 2,6,7-tri-substituted analogues of purine given in

Tables 1 and 2 are synthesised as described in (Scheme 1).

2,6 dichloropurine (4) was subjected for alkylation using

Medicinal Chemistry Research

Table 1 2,6,9-Tri-substituted analogues of purine

R₁

N

R₃

R₂

N

R₁

R₂

R₃

S.NO

H

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

Pyrolidine

Piperidine

9a

H₂N

H

9b

9c

9d

9e

9f

"

2-Cl

4-Cl

4-Br

9g

9h

9i

4-Br

2-Br

9j

4-F

9k

9l

4-F

2-F

9m

9n

9o

9p

9q

9r

9s

2-F

4-Br-2-Me

3-Br, 4-Me

4-OCH₃

4-F

9t

9u

9v

9w

9x

OH-CH₂-CH₂-NH₂

4-F

OH-CH₂-CH₂-NH₂

2-Br

"

4-Br, 2-Me

human cancer cell lines tested. Further, it was also observed

that while most of the synthesised analogues exhibited

considerable anticancer activity against leukaemia and lung-

derived cancer cell lines. However, compound 9a was

found to show potent anticancer activity on all the tested

cancer cell lines with IC₅₀values ranging from 0.08 to

18.9 μM. While compounds 9b and 9e showed potent

activity against three tested cancer cell lines, i.e., lung,

leukaemia and colon-derived cell lines. Majority of the

analogues were also found to show promising activity

against the above-mentioned three cancer cell lines.

In vitro anticancer activity of the N-7-substituted 1,2,3

triazole analogues of 2,6-di-substituted purine

N-7-substituted 1,2,3 triazole analogues of 2,6-di-sub-

stituted purine (12a–12e) were evaluated for in vitro

anticancer activity against a panel of four human cancer cell

lines like HCT-1 (colon), THP-1 (leukaemia), IMR-32

(neuroblastoma) and A-549 (lung). Table 4 summarises the

inhibitory activity values of analogues synthesised with

5-FU taken as standard drug. From the screening results, it

was observed that N-7-substituted compounds 12c and 12d

Medicinal Chemistry Research

Table 2 2,6,7-Tri-substituted analogues of purine

have shown potent cytotoxic activity against all the tested

cancer cell lines. While compounds 12a and 12b exhibited

signiﬁcant cytotoxicity on lung-derived cancer cell line.

N

R₃

R₁

Conclusion

N

Commercially available 2,6 dichloropurine was used as a

starting substrate for the synthesis of N-9 and N-7-substituted

1,2,3 triazolyl analogues. C6 position of purine scaffold was

substituted with amines like benzyl amine and aminoethanol,

and C2 position was substituted with cyclic secondary amines

like pyrolidine and piperidine. All the analogues were tested

for their cytotoxic activity against a panel of four human

cancer cell lines. Most of the synthesised derivatives of 2,6-

dichloropurine exhibited potent cytotoxicity with three of the

compounds 9a, 9b and 9e being most potent within the library

of analogues synthesised.

N

R₂

N

R₁

S.NO

12a

R₃

R₂

H

N

Pyrolidine

OCH₃

H

N

12b

OCH₃

4-CF3

Piperidine

Pyrolidine

12c

12d

12e

"

Pyrolidine

4I

"

4Br

Aminoethanol

DPX400 instrument was used to record the Nuclear Mag-

netic Resonance (NMR) spectra with samples taken in

CDCl₃. δ (ppm) was used to report chemical shift values

with coupling constants taken in Hertz. Electrospray ioni-

zation mass spectrometry (ESI MS) was used to record

Mass spectra. Monitoring of reactions was done by Thin

Layer Chromatography (TLC) on 2–5 cm percolated silica

gel 60 F₂₅₄plates of thickness 0.25 mm (Merck). UV

(254–366 nm) and iodine were used to visualise the

chromatograms.

R'

Benzylamine

N

pyrolidine

piperidine

N

"R

N

9(a-x)

General reaction procedure for synthesis of

compounds 5 and 6

R

Compound 4 (0.2 g, 1 mmol) taken in a two-necked

round-bottom ﬂask placed under conditions of inert

atmosphere was added K₂CO₃(0.2 g, 1.5 mmol) and

acetone (10 ml). The resulting mixture was stirred for few

minutes. To the mixture was then added propargyl bro-

mide (0.2 ml, 1.5 mmol) and the reaction mixture was

allowed to reﬂux at 60 °C for 2–3 h. The reaction mixture

was ﬁltered and concentrated under reduced pressure.

Water was added to the reaction mixture and transferred to

separatory funnel and extracted with Dichloromethane

(DCM). The organic layer was separated, dried with

anhydrous MgSO₄and concentrated on rota vapour.

Puriﬁcation of the crude material was done by ﬂash

chromatography and eluted with hexane/ethyl acetate.

Puriﬁed compounds (5) (90%) and (6) with 10% yield

were obtained as white crystals; ¹H NMR (400 MHz,

CDCl₃): δ 8.75 (s, 1H_8Pu), 5.10 (s, 2H_CH2Al), 2.11 (s,

1H_CHAl); ¹³C NMR (100 MHz, CDCl₃): 39.5 (CH₂), 67.0

While trying to generate the Structure Activity Relation-

ship (SAR) of the synthesised compounds, it was observed

that the activity depended on the substitution on the purine

ring. N-9-substituted triazole analogues were found to be

more active than N-7-substituted analogues. Further, analo-

gues with benzylamine substitution at C6 position were more

active. Activity also varied with the substitution on the aro-

matic rings attached to 1,2,3 triazole ring at N-9 position.

Order of activity observed with the various substituents was

H > F > Cl > Br > OCH₃. While C2 substitution did not effect

the activity to a much extent.

Experimental procedure

Buchi Melting point apparatus D-545 was used to record the

melting points of the synthesised compounds. Bruker

Medicinal Chemistry Research

Cl

N

Cl

N

Br

N

Cl

N

Acetone, rt, 3hr

Cl

N

H

Cl

N

6

K₂CO₃

5

4

Minor (20%)

Major (80%)

ΝΗ₂

OH

H₂N

ΝΗ₂

OH

/

H₂N

/

ΝΗ

Ν

ΝΗ

Ν

10

Cl

Ν

7

Ν₃

ΝΗ

Ν

R

Ν₃

Ν

N

Cl

Ν

N

R₃

R

R₁

Ν

N

8(a-x)

R'

Cl

N

11(a-x)

N

R

N

"R

N

R'

R

N

9(a-x)

R''

N

12(a-x)

Scheme 1 Synthesis of 2,6,9 and 2,6,7-tri-substituted purine analogues

(CH_Al), 80.3 (C_Al), 128.2 (C5_Pu), 144.6 (C4_Pu), 147.5

(C8_Pu), 150.0 (C2_Pu), 153.2 (C6_Pu); ESI MS: 225.0.

(0.13 g, 1.2 mmol) and diisopropylamine (0.19 g, 1.5 mmol),

and the reaction mixture was allowed to reﬂux at 90 °C for

12 h. The reaction mixture was ﬁltered and concentrated

under reduced pressure. Water was added to the reaction

mixture and transferred to separatory funnel and extracted

with DCM. The organic layer was separated, dried with

anhydrous MgSO4 and concentrated on rota vapour. Pur-

iﬁcation of the crude material was done by ﬂash chromato-

graphy and eluted with hexane/ethyl acetate. Puriﬁed

General reaction procedure for synthesis of

compound 7

Compound 6 (0.25 g, 1 mmol) was taken in a two-necked

round-bottom ﬂask, to which was added n-butanol (10 ml).

To the solution was added benzyl amine/ethanolamine

Medicinal Chemistry Research

compound (7) was obtained with 95% yield; ¹H NMR

(400 MHz, CDCl₃): δ 8.21 (s, 1H8_Pu), δ 7.30–7.20 (m, 5H_Ba),

5.20 (s, 2H_CH2Ba), 4.80 (s, 2H_CH2Al), 2.51 (s, 1H_CHAl); ¹³C

NMR (100 MHz, CDCl₃): 39.5 (CH₂), 67.0 (CH_Al), 80.3

(C_Al), 58.5_(CH2Ba), 126.5 (C_4Ba), 127.3 (C3_Ba, C5_Ba), 127.6

(C2_Ba, C6_Ba), 128.2 (C5Pu), 142.0 (C_1Ba), 144.6 (C4_Pu),

147.5 (C8_Pu), 150.0 (C2_Pu), 153.2 (C6_Pu); ESI MS: 297.0.

General reaction procedure for synthesis of

compound 8

Compound 7 (0.3, 1 mmol) and substituted aromatic azides

(0.1 g, 1.2 mmol) were taken in a 100 ml two-necked round-

bottom ﬂask. To the mixture was added CuSO₄·5H₂O (0.92,

0.5 mmol), sodium ascorbate (0.297, 2 mmol) and tBuOH:

H₂O 10 ml (1:1) mixture, and allowed to stir for few hours.

Water was added to the reaction mixture and transferred to

separatory funnel and extracted with ethylacetate. The

organic layer was separated, dried with anhydrous MgSO4,

and concentrated on rota vapour. Puriﬁcation of the crude

material was done by ﬂash chromatography and eluted with

hexane/ethyl acetate. Puriﬁed compounds of varying sub-

stituent’s on the phenyl ring were obtained with high yields.

General reaction procedure for synthesis of

compound 9

Compound 8 (0.416, 1 mmol) taken in a two-necked round-

bottom ﬂask placed under inert atmosphere was added

Fig. 2 X-Ray crystal structure of N-7-alkylated purine regioisomer

Fig. 3 X-ray crystal structure of compound 9g

Medicinal Chemistry Research

Table 3 N-9-substituted 1,2,3 triazolyl analogues of 2,6-di-substituted

purine and their anticancer activity against four human cancer cell

lines in IC₅₀values (μM)

concentrated on rota vapour. Puriﬁcation of the crude

material was done by ﬂash chromatography and eluted with

hexane/ethyl acetate. Puriﬁed compounds (9a–x) were

obtained with high yields.

Compounds A549

THP-1

HCT-15

IMR-32

9a

9b

9c

0.4

0.08

0.8

17

18.9

>50

28

General reaction procedure for synthesis of

compound 11

0.03

12

0.16

3.6

4.5

9d

9e

14

34

9.8

Compound 10 (0.416, 1 mmol) taken in a two-necked

round-bottom ﬂask placed under inert conditions was added

nBuOH (10 ml). To the solution was added pyrole/piper-

idine (0.14 ml, 2 mmol) and DIEA (0.19 ml, 1.5 mmol). The

reaction mixture was subjected to reﬂux for 24 h at 120 °C.

Water was added to the reaction mixture and transferred to

separatory funnel and extracted with ethylacetate. The

organic layer was separated, dried with anhydrous MgSO4,

and concentrated on rota vapour. Puriﬁcation of the crude

material was done by ﬂash chromatography and eluted with

hexane/ethyl acetate. Puriﬁed compound (11a–e) was

obtained with high yields.

0.12

15

0.7

0.66

18.9

>50

41.6

>50

16.4

6.4

>50

40.5

8.9

9f

18.7

28.3

12.6

8.2

9g

9h

9i

13.7

21.5

4.5

13.9

0.5

9j

0.68

0.14

1.6

2.6

12

9k

9l

0.53

1.5

28

46

9m

9n

9o

9p

9q

9r

2.3

2.5

32

2.1

3.2

19

1.2

5.7

14

13

2.1

5.5

32

21

24

38.4

40.5

21.8

26

42.1

>50

14.7

>50

40.8

19.5

6.8

>50

42.1

>50

12.4

23.4

4.5

24.6

45.2

43

Compound characterisation

9s

9t

Benzyl-[9-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-2-

pyrrolidin-1-yl-9H-purin-6-yl]-amine (9a)

9u

9v

9w

9x

5-FU

17.8

>50

18

32.1

28.7

13.2

12.4

1

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white crystalline solid with

90% Yield; mp: 156–157 °C; ¹H NMR (400 MHz, CDCl₃):

δ 8.10 (s, 1H_8Pu), 7.75 (s, 1H_5T), 7.50 (m, 5H_Ph), 7.45 (m,

5H_Ba), 5.40 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T), 2.00 (m, 2H₁,

2H_4(CH2Py)), 1.35 (m, 2H₂, 2H_3(CH2Py)); ¹³C (100 MHz,

CDCl₃): 23.7 (C1, C4_(CH2py)), 45.2 (C2, C3_(CH2py)),

50.3_(CH2T)), 58.5_(CH2Ba), 126.5 (C_4Ba), 127.3 (C3_Ba, C5_Ba),

127.6 (C2_Ba, C6_Ba), 128.6 (C3_Ph, C4_Ph, C5_Ph), 128.7 (C1_Ph,

C2_Ph, C6_Ph), 138.2 (C5_T, C5_Pu), 143.6 (C3_Pu, C1_Ba), 152.0

(C1_T), 155.2 (C2_Pu), 155.3 (C4_Pu, C8_Pu), 158.0 (C6_Pu); ESI

MS: 452 (M⁺); Anal. calcd. for C₂₅H₂₅N₉: C, 66.50; H,

5.58; Found: C, 66.45; H, 5.54.

>50

4.9

8.7

6

Table 4 N-7-substituted 1,2,3 triazolyl analogues of 2,6-di-substituted

purine and their anticancer activity against four human cancer cell

lines in IC₅₀values (μM)

Compounds

A549

THP-1

HCT-15

IMR-32

9a

9.8

5.6

20

11.0

13.6

12.3

16.5

1

43.2

>50

20.2

13.5

6

>50

45

9b

9c

9d

16

23

5-FU

4.9

4.5

Benzyl-[9-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-2-

piperidin-1-yl-9H-purin-6-yl]-amine (9b)

nBuOH (10 ml). To the solution was added pyrolidine/

piperidine (0.14 ml, 2 mmol) and N,N-Diisopropylethyla-

mine (DIEA) (0.19 ml, 1.5 mmol). The reaction mixture was

reﬂuxed for 24 h at 120 °C. The reaction mixture was ﬁl-

tered and concentrated under reduced pressure. Water was

added to the reaction mixture and transferred to separatory

funnel and extracted with ethylacetate. The organic layer

was separated, dried with anhydrous MgSO₄, and

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white solid with 80% Yield;

1

mp: 170–172 °C; H NMR (400 MHz, CDCl₃): δ 8.10 (s,

1H_8Pu), 7.75 (s, 1H_5T), 7.50 (m, 5H_Ph), 7.45 (m, 5H_Ba), 5.40

(s, 2H_CH2Ba), 4.60 (s, 2H_CH2T), 2.20 (m, 2H₁, 2H_5(CH2Pi)),

1.50–1.45 (m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz,

CDCl₃): 25.1 (C2, C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)),

Medicinal Chemistry Research

126.5 (C_4Ba), 127.3 (C3_Ba, C5_Ba), 127.6 (C2_Ba, C6_Ba),128.6

(C3_Ph, C4_Ph, C5_Ph), 128.7 (C1_Ph, C2_Ph, C6_Ph), 138.2 (C5_T,

C5_Pu), 143.6 (C3_Pu, C1_Ba), 152.0 (C1_T), 155.2 (C2Pu),

155.3 (C4_Pu, C8_Pu), 158.0 (C6_Pu); ESI MS: 466 (M⁺); Anal.

calcd. for C₂₆H₂₇N₉: C, 67.08; H, 5.85; Found: C, 66.93;

H, 5.04.

(s, 2H_CH2Ba), 5.30 (s, 2H_CH2T), 2.20 (m, 2H₁, 2H_4(CH2Py)), 1.30

(m, 2H₂, 2H_3(CH2Py)); ¹³C (100 MHz, CDCl₃): 23.7(C1,

C4_(CH2py)), 45.2 (C2, C3_(CH2py)), 50.3_(CH2T)), 58.5_(CH2Ba)

,

126.5 (C_4Ba), 127.3 (C2_Ba, C6_Ba, C5_Ph), 128.0 (C3_Ba, C5_Ba),

129.0 (C1_Ph, C3_Ph), 130.7 (C6_Ph, C5_T), 134.0 (C6_Ph), 138.2

(C1_T, C5_Pu), 143.6 (C3_Pu, C1_Ba), 155.2 (C2_Pu), 155.3 (C4_Pu,

C8_Pu), 158.0 (C6_Pu); ESI MS: 486 (M⁺); Anal. calcd. for

C₂₅H₂₄ClN₉: C, 61.79; H, 4.85; Found: C, 60.45; H, 5.40.

Benzyl-{9-[1-(2-chloro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9c)

Benzyl-{9-[1-(4-chloro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9f)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for synthesis

of compound 9’ as white crystalline solid with 92% Yield;

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for synthesis

of compound 9’ as white solid with 80% Yield; mp:

168–169 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H_8Pu),

7.85 (s, 1H_5T), 7.70 (d, 1H3_Ph, 1H5_Ph, J = 8.4 Hz), 7.50 (d,

1H2_Ph, 1H4_Ph, J = 7.5 Hz), 7.30–7.20 (m, 5H_Ba), 5.40 (s,

2H_CH2Ba), 5.30 (s, 2H_CH2T), 2.80–2.60 (m, 2H₁, 2H_5(CH2Pi)),

1.60–1.59 (m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz, CDCl₃):

25.1 (C2, C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.3_(CH2T)),

58.5_(CH2Ba), 126.0 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C5_Ph), 128.0

(C3_Ba, C5_Ba), 129.0 (C1_Ph, C3_Ph), 130.0 (C6_Ph, C5_T), 134.0

(C6_Ph), 138.0 (C1_T, C5_Pu), 143.0 (C3_Pu, C1_Ba), 155.0 (C2_Pu),

155.0 (C4_Pu, C8_Pu), 158.0 (C6_Pu); ESI MS: 500 (M⁺); Anal.

calcd. for C₂₆H₂₆ClN₉: C, 62.46; H, 5.24; Found: C, 61.93;

H, 5.04.

1

mp: 150–151 °C; H NMR (400 MHz, CDCl₃): δ 8.18 (s,

1H_8Pu), 7.75 (s, 1H_5T), 7.20–7.10 (m, 4H_Ph), 7.05–7.00 (m,

5H_Ba), 5.50 (s, H_CH2Ba), 4.90 (s, 2H_CH2T), 2.7–2.6 (m, 2H₁,

2H_4(CH2Py)), 1.50–1.45 (m, 2H₂, 2H_3(CH2Py)); ¹³C (100 MHz,

CDCl₃): 24.6 (C1)_(CH2py), 25.9 (C4)_(CH2py)), 47.2 (C2,

C3_(CH2py)), 50.8_(CH2T)), 58.5_(CH2Ba), 126.5 (C_4Ba), 127.3 (C2_Ba,

C6_Ba, C5_Ph), 128.0 (C3_Ba, C5_Ba), 129.0 (C1_Ph, C3_Ph), 130.7

(C4_Ph, C6_Ph), 133.0 (C2_Ph), 136.2 (C5_T, C5_Pu), 144.7 (C3_Pu,

C1_Ba), 150.0 (C1_T), 154.2 (C2_Pu), 157.3 (C4_Pu, C8_Pu), 158.0

(C6_Pu); ESI MS: 486 (M⁺); Anal. calcd. for C₂₅H₂₄ClN₉: C,

61.79; H, 4.85; Found: C, 60.45; H, 5.40.

Benzyl-{9-[1-(2-chloro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9d)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white crystalline solid with

85% Yield; mp: 170–171 °C; ¹H NMR (400 MHz, CDCl₃):

δ 8.68 (s, 1H_8Pu), 7.75 (s, 1H_5T), 7.20–7.10 (m, 4H_Ph),

7.05–7.00 (m, 5H_Ba), 5.50 (s, 2H_CH2Ba), 4.90 (s, 2H_CH2T),

2.8–2.6 (m, 2H₁, 2H_5(CH2Pi)), 1.60–1.59 (m, 2H₂, 2H₃

, 2H_4(CH2Pi)); ¹³C (100 MHz, CDCl₃): 29.5 (C2, C3), 31.9

(C4)_(CH2pi), 44.0 (C1), 46.0 (C5_(CH2pi), 50.0_(CH2T)), 58.5

_(CH2Ba), 122.5 (C_4Ba), 123.1 (C2_Ba), 123.9 (C6_Ba, C5_Ph),

125.0 (C3_Ba), 128.0 (C5_Ba), 132.5 (C1_Ph, C3_Ph), 133.8

(C4_Ph, C6_Ph), 134.5 (C2_Ph), 134.8 (C5_T, C5_Pu), 149.9 (C3_Pu,

C1_Ba), 151.3 (C1_T), 152.6 (C2Pu), 152.8 (C4_Pu, C8_Pu),

154.7 (C6_Pu); ESI MS: 500 (M⁺); Anal. calcd. for

C₂₆H₂₆ClN₉: C, 62.46; H, 5.24; Found: C, 61.93; H, 5.04.

Benzyl-{9-[1-(2-bromo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9g)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white solid with 95% Yield;

1

mp: 155–157 °C; H NMR (400 MHz, CDCl₃): δ 8.75 (s,

1H_8Pu), 8.35 (s, 1H_5T), 7.70 (m, 4H_Ph), 7.30–7.20 (m, 5H_Ba),

5.50 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T), 2.7–2.6 (m, 2H₁,

2H_4(CH2Py)), 1.60 (m, 2H₂, 2H_{3(CH2Py) (CH2Py)}

); ¹³C

)

(100 MHz, CDCl₃): 29.6 (C1, C4_(CH2py)), 45.6 (C2,

C3_(CH2py)), 50.2_(CH2T)), 60.0_(CH2Ba), 110.7 (C1_Ph), 126.7

(C_4Ba), 127.1 (C2_Ba, C6_Ba, C5_Ph), 128.0 (C3_Ba, C5_Ba), 128.8

(C1_Ph, C3_Ph), 137.5 (C5_Ph, C5_T), 134.0 (C6_Ph), 138.2 (C1_T,

C5_Pu), 144.6 (C3_Pu, C1_Ba, C8_Pu), 151.2 (C2_Pu), 154.3 (C4_Pu),

157.5 (C6_Pu); ESI MS: 530 (M⁺); Anal. calcd. for

C₂₅H₂₄BrN₉: C, 67.50; H, 5.85; Found: C, 66.45; H, 5.54.

Benzyl-{9-[1-(4-chloro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9e)

Benzyl-{9-[1-(2-bromo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9h)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for synthesis

of compound 9’ as white solid with 95% Yield; mp:

158–159 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H_8Pu),

7.85 (s, 1H_5T), 7.70 (d, 1H3_Ph, 1H5_Ph, J = 8.4 Hz), 7.50

(d, 1H2_Ph, 1H4_Ph, J = 7.5 Hz), 7.30–7.20 (m, 5H_Ba), 5.40

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for synthesis

of compound 9’ as white solid with 85% Yield; mp:

172–173 °C; ¹H NMR (400 MHz, CDCl₃):

δ

8.75

Medicinal Chemistry Research

1

(s, 1H_8Pu), 8.35 (s, 1H_5T), 7.70 (m, 4H_Ph), 7.30–7.20 (m,

5H_Ba), 5.50 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T), 2.8–2.6 (m, 2H₁,

2H_5(CH2Pi)), 1.60–1.59 (m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C

154–155 °C; H NMR (400 MHz, CDCl₃): δ 8.30 (s, 1H_8Pu),

7.85 (s, 1H_5T), 7.30–7.20 (m, 4H_Ph, 5H_Ba), 5.60 (s, 2H_CH2Ba),

4.90 (s, 2H_CH2T), 2.50 (m, 2H₁, 2H_4(CH2Py)), 1.59 (m, 2H₂,

2H_3(CH2Py)); ¹³C (100 MHz, CDCl₃): 23.0 (C1,

(100 MHz, CDCl₃): 24.6 (C2, C3)_(CH2pi), 25.9 (C4)_(CH2pi)

,

50.8 (C1, C5_(CH2pi)), 50.3_(CH2T)), 58.5_(CH2Ba), 124.0 (C1_Ph),

126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C5_Ph), 128.0 (C3_Ba, C5_Ba,

C4_Ph), 129.0 (C1_Ph, C3_Ph), 130.7 (C5_T), 134.0 (C6_Ph), 138.2

(C1_T, C5_Pu), 143.6 (C3_Pu, C1_Ba),145.0 (C8_Pu), 155.2 (C2_Pu),

155.3 (C4_Pu), 158.0 (C6_Pu); ESI MS: 544 (M⁺); Anal. calcd.

for C₂₆H₂₆BrN₉: C, 57.36; H, 4.81; Found: C, 56.80; H, 4.35.

C4_(CH2py)), 45.0 (C2, C3_(CH2py)), 50.0_(CH2T)), 58.0_(CH2Ba),

116.0 (C2_Ph, C3_Ph), 123.0 (C5_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba,

C6_Ba), 128.0 (C3_Ba, C5_Ba), 130.0 (C4_Ph, C5_T), 138.2 (C1_T,

C5_Pu), 143.6 (C1_Ba), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu),

158.0 (C6_Pu); 162.0 (C1_Ph); ESI MS: 470 (M⁺); Anal. calcd.

for C₂₅H₂FN₉: C, 63.50; H, 5.15; Found: C, 63.45; H, 5.04.

Benzyl-{9-[1-(4-bromo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9i)

Benzyl-{9-[1-(2-ﬂuoro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9l)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white solid with 95% Yield;

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white solid with 80% Yield;

1

mp: 157–158 °C; H NMR (400 MHz, CDCl₃): δ 8.20 (s,

mp: 170–171 °C; H NMR (400 MHz, CDCl₃): δ 8.30 (s,

1H_8Pu), 7.75 (s, 1H_5T), 7.60 (d, 1H3_{Ph, 1}H5_Ph), 7.25 (d,

1H2_Ph, 1H6_Ph), 7.10–7.00 (m, 5H_Ba), 5.40 (s, 2H_CH2Ba), 4.90

(s, 2H_CH2T), 2.00 (m, 2H₁, 2H_4(CH2Py)), 1.30 (m, 2H₂,

1H_8Pu), 7.85 (s, 1H_5T), 7.30–7.20 (m, 4H_Ph, 5H_Ba), 5.60 (s,

2H_CH2Ba), 4.90 (s, 2H_CH2T), 2.8–2.6 (m, 2H₁, 2H_5(CH2Pi)),

1.60–1.59 (m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz,

CDCl₃): 25.1 (C2, C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)),

50.5_(CH2T)), 58.5_(CH2Ba), 116.0 (C2_Ph, C3_Ph), 123.0 (C5_Ph),

126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba), 128.0 (C3_Ba, C5_Ba), 130.0

(C4_Ph, C5_T), 138.2 (C1_T, C5_Pu), 143.6 (C1_Ba), 145.0 (C8_Pu),

155.2 (C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu); 162.0 (C1_Ph); ESI

MS: 483 (M⁺); Anal. calcd. for C₂₆H₂₆FN₉: C, 64.58; H,

5.42; Found: C, 64.02; H, 5.40.

2H_3(CH2Py))_;

¹³C (100 MHz, CDCl₃): 23.0 (C1, C4_(CH2py)),

45.0 (C2, C3_(CH2py)), 50.0_(CH2T)), 58.0_(CH2Ba), 123.0 (C4_Ph),

126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba), 128.0 (C3_Ba, C5_Ba), 130.0

(C1_Ph, C2_Ph, C6_Ph), 132.0 (C3_Ph, C5_Ph, C5_T), 138.2 (C1_T,

C5_Pu), 143.6 (C1_Ba), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3

(C4_Pu), 158.0 (C6_Pu); ESI MS: 530 (M⁺); Anal. calcd. for

C₂₅H₂₄BrN₉: C, 67.50; H, 5.85; Found: C, 66.45; H, 5.54.

Benzyl-{9-[1-(4-bromo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9j)

Benzyl-{9-[1-(4-ﬂuoro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9m)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’ as white solid with 80% Yield;

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for synthesis

of compound 9’ as white solid with 92% Yield; mp:

155–157 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.65 (s, 1H_8Pu),

7.75 (s, H_5T), 7.20 (d, 1H_2Ph, 1H_6Ph, J = 5.4 Hz), 7.15 (d,

1H_3Ph, 1H_5Ph, J = 6.2 Hz), 7.00 (m, 5H_Ba), 5.50 (s, 2H_CH2Ba),

4.90 (s, 2H_CH2T), 2.8–2.6 (m, 2H₁, 2H_4(CH2Py)), 1.60–1.59 (m,

2H₂, 2H_3(CH2Py)); ¹³C (100 MHz, CDCl₃): 23.0 (C1, C4

1

mp: 172–173 °C; H NMR (400 MHz, CDCl₃): δ 8.10 (s,

1H_8Pu), 7.75 (s, 1H_5T), 7.60 (d, 1H3_Ph, 1H5_Ph), 7.25 (d,

1H2_Ph, 1H6_Ph), 7.10–7.00 (m, 5H_Ba), 5.50 (s, 2H_CH2Ba), 4.90

(s, 2H_CH2T), 2.8–2.6 (m, 2H₁, 2H_5(CH2Pi)), 1.80 (m, 2H₂,

2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz, CDCl₃): 25.1 (C2, C3,

C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.8_(CH2T)), 58.4_(CH2Ba)

,

_(CH2py)), 45.0 (C2, C3_(CH2py)), 50.0_(CH2T)), 58.0_(CH2Ba),

113.4 (C4_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba), 128.0

(C3_Ba, C5_Ba), 132.9 (C1_Ph, C2_Ph, C6_Ph, C3_Ph, C5_Ph, C5_T),

138.2 (C1_T, C5_Pu), 143.6 (C1_Ba, C8_Pu), 150.2 (C2_Pu), 157.3

(C4_Pu), 158.0 (C6_Pu); ESI MS: 544 (M⁺); Anal. calcd. for

C₂₆H₂₆BrN₉: C, 57.36; H, 4.81; Found: C, 56.80; H, 4.35.

116.0 (C3_Ph, C5_Ph), 123.0 (C1_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba,

C6_Ba), 128.0 (C3_Ba, C5_Ba), 130.0 (C2_Ph, C6_Ph, C5_T), 138.2

(C1_T, C5_Pu), 143.6 (C1_Ba), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3

(C4_Pu), 158.0 (C6_Pu); 162.0 (C1_Ph); ESI MS: 470 (M⁺); Anal.

calcd. for C₂₅H₂₄FN₉: C, 63.50; H, 5.15; Found: C, 63.45;

H, 5.04.

Benzyl-{9-[1-(2-ﬂuoro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9k)

Benzyl-{9-[1-(4-ﬂuoro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9n)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for synthesis

of compound 9’ as white solid with 90% Yield; mp:

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

Medicinal Chemistry Research

synthesis of compound 9’ as white solid with 75% Yield;

mp: 165–166 °C; H NMR (400 MHz, CDCl₃): δ 8.65 (s,

1H_8Pu), 7.75 (s, H_5T), 7.20 (d, 1H_2Ph, 1H_6Ph, J = 5.4 Hz),

7.15 (d, 1H_3Ph, 1H_5Ph, J = 6.2 Hz), 7.00 (m, 5H_Ba), 5.50 (s,

2H_CH2Ba), 4.90 (s, 2H_CH2T), 2.6 (m, 2H₁, 2H_5(CH2Pi)), 1.39

(m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz, CDCl₃): 25.1 (C2,

Benzyl-{9-[1-(3-bromo-4-methyl-phenyl)-1H-[1,2,3]

triazol-4-ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-

amine (9q)

1

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.5_(CH2T)), 58.5_(CH2Ba)

,

1

116.0 (C3_Ph, C5_Ph),123.0 (C1_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba,

C6_Ba), 128.0 (C3_Ba, C5_Ba), 130.0 (C2_Ph, C6_Ph, C5_T), 138.2

(C1_T, C5_Pu), 143.6 (C1_Ba), 145.0 (C8_Pu), 155.2

(C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu); 162.0 (C1_Ph); ESI MS:

483 (M⁺); Anal. calcd. for C₂₆H₂₆FN₉: C, 64.58; H, 5.42;

Found: C, 64.02; H, 5.40.

with 92% Yield; mp: 155–157 °C; H NMR (400 MHz,

CDCl₃): δ 8.70 (s, 1H_8Pu), 8.30 (s, 1H_5T), 8.20 (s, 1H_2Ph),

7.80 (d, 1H_2Ph, J = 4.5 Hz), 7.50 (d, 1H_6Ph, J = 5.5 Hz),

7.30–7.20 (m, 5H_Ba), 5.50 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T),

3.30(m, 2H₁, 2H_4(CH2Py), 2.50 (s, 3H_CH3), 2.30 (m, 2H₂,

2H_3(CH2Py)); ¹³C (100 MHz, CDCl₃): 13.5 (CH₃), 23.5 (C1,

C4_(CH2py)), 45.0 (C2, C3_(CH2py)), 50.0_(CH2T)), 58.0_(CH2Ba)

,

Benzyl-{9-[1-(4-bromo-2-methyl-phenyl)-1H-[1,2,3]

triazol-4-ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-

amine (9o)

124.0 (C3_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph), 128.0

(C3_Ba, C5_Ba, C5_Pu), 132.0 (C2_Ph, C5_Ph, C5_T), 140.2 (C1_Ba,

C4_Ph), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0

(C6_Pu); ESI MS: 544 (M⁺); Anal. calcd. for C₂₆H₂₆BrN₉: C,

57.36; H, 4.81; Found: C, 55.45; H, 4.04.

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

Benzyl-{9-[1-(3-bromo-4-methyl-phenyl)-1H-[1,2,3]

triazol-4-ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-

amine (9r)

1

with 75% Yield; mp: 160–161 °C; H NMR (400 MHz,

CDCl₃): δ 8.90 (s, 1H_8Pu), 8.83 (s, H_5T), 7.30–7.20 (m,

2H_Ph, 5H_Ba), 7.00 (d, 1H_6Ph), 4.70 (s, 2H_CH2Ba), 4.30 (s,

2H_CH2T), 3.1 (m, 2H₁, 2H_4(CH2Py)), 2.50 (s, 3H_CH3), 1.70 (m,

2H₂, 2H_{3, (CH2Py)}); ¹³C (100 MHz, CDCl₃): 12.5 (CH₃), 23.0

(C1, C4_(CH2py)), 45.0 (C2, C3_(CH2py)), 50.0_(CH2T)),

58.0_(CH2Ba), 123.0 (C4_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba),

128.0 (C3_Ba, C5_Ba, C5_Pu), 129.0 (C1_Ph, C5_Ph), 130.0 (C3_Ph,

C6_Ph, C5_T), 133.0 (C1_T), 140.2 (C1_Ba), 145.0 (C8_Pu), 155.2

(C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu); ESI MS: 544 (M⁺);

Anal. calcd. for C₂₆H₂₆BrN₉: C, 57.36; H, 4.81; Found: C,

55.45; H, 4.04.

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

1

with 75% Yield; mp: 160–161 °C; H NMR (400 MHz,

CDCl₃): δ 8.70 (s, 1H_8Pu), 8.30 (s, 1H_5T), 8.20 (s, 1H_2Ph),

7.80 (d, 1H_2Ph, J = 4.5 Hz), 7.50 (d, 1H_6Ph, J = 5.5 Hz),

7.30–7.20 (m, 5H_Ba), 5.50 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T),

2.80 (m, 2H₁, 2H_5(CH2Pi), 2.50 (s, 3H_CH3), 1.80 (m, 2H₂,

2H_3(CH2Pi)); ¹³C (100 MHz, CDCl₃): 13.5(CH₃), 25.1 (C2,

C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.5_(CH2T)), 58.5_(CH2Ba)

,

Benzyl-{9-[1-(4-bromo-2-methyl-phenyl)-1H-[1,2,3]

triazol-4-ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-

amine (9p)

124.0 (C3_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph), 128.0

(C3_Ba, C5_Ba, C5_Pu), 132.0 (C2_Ph, C5_Ph, C5_T), 140.2 (C1_Ba,

C4_Ph), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0

(C6_Pu); ESI MS: 558 (M⁺); Anal. calcd. for C₂₇H₂₈BrN₉: C,

58.08; H, 5.02; Found: C, 58.02; H, 5.40.

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

Benzyl-{9-[1-(4-methoxy-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-yl}-amine (9s)

1

with 75% Yield; mp: 165–166 °C; H NMR (400 MHz,

CDCl₃): 8.90 (s, 1H_8Pu), 8.83 (s, H_5T), 7.30–7.20 (m, 2H_Ph,

5H_Ba), 7.00 (d, 1H_6Ph), 4.70 (s, 2H_CH2Ba), 4.30 (s, 2H_CH2T),

2.8–2.6 (m, 2H₁, 2H_5(CH2Pi)), 2.50 (s, 3H_CH3), 1.60–1.59 (m,

2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz, CDCl₃): 12.5(CH₃),

25.1(C2, C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.5_(CH2T)),

58.5_(CH2Ba), 123.0 (C4_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba),

128.0 (C3_Ba, C5_Ba, C5_Pu), 129.0 (C1_Ph, C5_Ph), 130.0 (C3_Ph,

C6_Ph, C5_T), 133.0(C1_T), 140.2 (C1_Ba), 145.0 (C8_Pu), 155.2

(C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu); ESI MS: 558 (M⁺);

Anal. calcd. for C₂₇H₂₈BrN₉: C, 58.08; H, 5.02; Found: C,

58.02; H, 5.40.

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

1

with 87% Yield; mp: 150–152 °C; H NMR (400 MHz,

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.70 (s, 1H_5T), 7.20 (d, 1H_2Ph

,

1H_6Ph), 7.10–7.00 (m, 5H_Ba), 6.80 (d, 1H_3Ph, 1H_5Ph), 5.50 (s,

2H_CH2Ba), 4.60 (s, 2H_CH2T), 3.50 (s, 3H_OCH3), 2.50 (m, 2H₁,

2H_4(CH2Py), 1.80 (m, 2H₂, 2H_3(CH2Py)); ¹³C (100 MHz,

CDCl₃): 23.0 (C2, C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)),

50.5_(CH2T)), 56.0_(OCH3), 58.5_(CH2Ba), 110.0 (C3_Ph, C5_Ph),

Medicinal Chemistry Research

120.0 (C1_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph), 128.0

(C3_Ba, C5_Ba, C5_Pu), 132.0 (C2_Ph, C5_T), 140.2 (C1_Ba), 145.0

(C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu), 162.0

(C4_Ph); ESI MS: 544 (M⁺); Anal. calcd. for C₂₆H₂₇N₉O: C,

64.85; H, 5.65; Found: C, 64.45; H, 5.06.

1H_6Ph), 7.10 (d, 1H_3Ph, 1H_5Ph), 5.00 (s, 2H_CH2Ba), 3.76 (t,

3H_CH2Ea), 3.50(t, 3H_CH2Ea), 3.00 (m, 2H₁, 2H_5(CH2Pi)), 1.50

(m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz, CDCl₃): 25.0 (C2,

C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.5_(CH2T)), 54.5_(CH2Ea)

,

60.0_(CH2Ea), 115.0 (C3_Ph, C5_Ph), 124.0 (C1_Ph), 128.0 (C5_Pu),

130.0 (C2_Ph, C6_Ph), 132.0 (C5_T), 145.0 (C8_Pu, C1_T), 155.2

(C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu), 162.0 (C4_Ph); ESI MS:

438 (M⁺); Anal. calcd. for C₂₁H₂₄FN₉O: C, 57.65; H, 5.53;

Found: C, 57.45; H, 5.14.

Benzyl-{9-[1-(4-methoxy-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-yl}-amine (9t)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

2-{9-[1-(2-bromo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-ylamino}-

ethanol (9w)

1

with 75% Yield; mp: 160–162 °C; H NMR (400 MHz,

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.70 (s, 1H_5T), 7.20 (d, 1H_2Ph

,

1H_6Ph), 7.10–7.00 (m, 5H_Ba), 6.80 (d, 1H_3Ph, 1H_5Ph), 5.50 (s,

2H_CH2Ba), 4.60 (s, 2H_CH2T), 3.50 (s, 3H_OCH3), 3.30 (m, 2H₁,

2H_5(CH2Pi)), 2.30 (m, 2H₂, 2H₃, 2H_4(CH2Pi)); ¹³C (100 MHz,

CDCl₃): 25.1 (C2, C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)),

50.5_(CH2T)), 58.5_(CH2Ba), 56.0_(OCH3), 58.5_(CH2Ba), 110.0 (C3_Ph,

C5_Ph), 120.0 (C1_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph),

128.0 (C3_Ba, C5_Ba, C5_Pu), 132.0 (C2_Ph, C5_T), 140.2 (C1_Ba),

145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu),

162.0 (C4_Ph); ESI MS: 496 (M⁺); Anal. calcd. for

C₂₇H₂₉N₉O: C, 65.48; H, 5.92; Found: C, 64.02; H, 5.69.

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

1

with 75% Yield; mp: 157–158 °C; H NMR (400 MHz,

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.75 (s, 1H_5T), 7.40 (d, 1H_3Ph),

7.20 (m, 1H_4Ph, 1H_5Ph,1H_6Ph), 5.00 (s, 2H_CH2Ba), 3.76 (t,

3H_CH2Ea), 3.50 (t, 3H_CH2Ea), 2.80 (m, 2H₁, 2H_4(CH2Py)), 1.80

(m, 2H₂, 2H_3(CH2Py)); ¹³C (100 MHz, CDCl₃): 23.0 (C2,

C3_(CH2py)), 45.3 (C1, C4_(CH2py)), 50.5_(CH2T)), 54.5_(CH2Ea)

,

60.0_(CH2Ea), 123.0 (C2_Ph), 128.0 (C5_Pu, C5_Ph), 131.0 (C4_Ph,

C6_Ph), 132.0 (C5_T, C1_Ph, C3_Ph), 145.0 (C8_Pu, C1_T), 155.2

(C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu); ESI MS: 487 (M⁺);

Anal. calcd. for C₂₀H₂₂BrN₉O: C, 49.50; H, 4.55; Found: C,

46.55; H, 4.54.

2-{9-[1-(4-Fluoro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-9H-purin-6-ylamino}-

ethanol (9u)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

2-{9-[1-(4-Bromo-2-methyl-phenyl)-1H-[1,2,3]triazol-

4-ylmethyl]-2-piperidine-1-yl-9H-purin-6-ylamino}-

ethanol (9x)

1

with 75% Yield; mp: 160–162 °C; H NMR (400 MHz,

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.75 (s, 1H_5T), 7.20 (d, 1H_2Ph

,

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

1H_6Ph), 7.10 (d, 1H_3Ph, 1H_5Ph), 5.00 (s, 2H_CH2Ba), 3.76 (t,

3H_CH2Ea), 3.50 (t, 3H_CH2Ea), 2.80 (m, 2H₁, 2H_4(CH2Py)), 1.80

(m, 2H₂, 2H_3(CH2Py)); ¹³C (100 MHz, CDCl₃): 23.0 (C2,

1

with 76% Yield; mp: 148–150 °C; H NMR (400 MHz,

C3_(CH2py)), 45.3 (C1, C4_(CH2py)), 50.5_(CH2T)), 54.5_(CH2Ea)

,

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.75 (s, 1H_5T), 7.20 (m, 1H_3Ph,

60.0_(CH2Ea), 115.0(C3_Ph, C5_Ph), 124.0 (C1_Ph), 128.0 (C5_Pu),

130.0 (C2_Ph, C6_Ph), 132.0 (C5_T), 145.0 (C8_Pu, C1_T), 155.2

(C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu), 162.0 (C4_Ph); ESI MS:

423 (M⁺); Anal. calcd. for C₂₀H₂₂FN₉O: C, 56.73; H, 5.25;

Found: C, 56.45; H, 5.04.

1H_5Ph), 7.10 (d, 1H_6Ph), 5.00 (s, 2H_CH2Ba), 3.76 (t, 3H_CH2Ea),

3.50 (t, 3H_CH2Ea), 3.00 (m, 2H₁, 2H_5(CH2Pi)), 2.30 (s, 3H_CH3),

1.80 (m, 2H₂, 2H₃, 2H4_(CH2Pi)); ¹³C (100 MHz, CDCl₃):

10.5 (CH₃), 25.0 (C2, C3, C4_(CH2pi)), 45.3 (C1, C5_(CH2pi)),

50.5 (CH₂T)), 54.5 (CH₂Ea), 60.0 (CH₂Ea), 123.0 (C4_Ph),

128.0 (C5_Pu, C1_Ph), 129.0 (C5_Ph), 130.0 (C6_Ph), 132.0 (C5_T,

C3_Ph), 145.0 (C8_Pu, C1_T), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0

(C6_Pu); ESI MS: 512 (M⁺); Anal. calcd. for C₂₂H₂₆BrN₉O:

C, 51.57; H, 5.11; Found: C, 51.45; H, 5.10.

2-{9-[1-(4-Fluoro-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-9H-purin-6-ylamino}-

ethanol (9v)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 9’. It was obtained as a white solid

Benzyl-{7-[1-(4-methoxy-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-7H-purin-6-yl}-amine (12a)

1

with 76% Yield; mp: 148–149 °C; H NMR (400 MHz,

This compound was prepared according to the procedure

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.75 (s, 1H_5T), 7.20 (d, 1H_2Ph

,

given in the section ‘General reaction procedure for

Medicinal Chemistry Research

synthesis of compound 11’. It was obtained as a white solid

with 78% Yield; mp: 157–158 °C; H NMR (400 MHz,

(C4_Pu), 158.0 (C6_Pu); ESI MS: 520 (M⁺); Anal. calcd. for

C₂₆H₂₄F₃N₉: C, 60.11; H, 4.66; Found: C, 60.05; H, 4.54.

1

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.70 (s, 1H_5T), 7.20 (d, 1H_2Ph

,

1H_6Ph), 7.10–7.00 (m, 5H_Ba), 6.80 (d, 1H_3Ph, 1H_5Ph), 5.50 (s,

2H_CH2Ba), 4.60 (s, 2H_CH2T), 3.50 (s, 3H_OCH3), 2.75 (m,

2H2_CH2py), 2H3_CH2py), 1.80 (m, H₂, H_3(CH2Py)); ¹³C

(100 MHz, CDCl₃): 23.0 (C2, C3_(CH2pi)), 50.3 (C1,

C4_(CH2pi)), 50.5_(CH2T)), 56.0_(OCH3), 58.5_(CH2Ba), 110.0 (C3_Ph,

C5_Ph), 120.0 (C1_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph),

128.0 (C3_Ba, C5_Ba, C5_Pu), 132.0 (C2_Ph, C5_T), 140.2 (C1_Ba),

145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu),

162.0 (C4_Ph); ESI MS: 482 (M⁺); Anal. calcd. for

C₂₆H₂₇N₉O: C, 64.80; H, 5.65; Found: C, 64.55; H, 5.54.

Benzyl-{7-[1-(4-bromo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-7H-purin-6-yl}-amine

(12d)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 11’. It was obtained as a white solid

1

with 80% Yield; mp: 152–153 °C; H NMR (400 MHz,

CDCl₃): δ 8.70 (s, 1H_8Pu), 8.50 (s, 1H_5T), 7.40 (d, 1H_3Ph

,

1H_5Ph, J = 7.8 Hz), 7.30 (d, 1H_2Ph, 1H_6Ph, J = 6.8 Hz),

7.10–7.00 (m, 5H_Ba), 5.90 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T),

2.75 (m, 2H2_CH2py), 2H3_CH2py), 1.80 (m, 2H₂, 2H_3(CH2Py));

¹³C (100 MHz, CDCl₃): 23.0 (C2, C3_(CH2pi)), 50.3 (C1,

C4_(CH2pi)), 50.5_(CH2T)), 58.5_(CH2Ba), 123.0 (C4_Ph), 126.5

(C_4Ba), 127.0 (C2_Ba, C6_Ba, C1_Ph), 128.0 (C3_Ba, C5_Ba, C5_Pu,

C1_Ph), 131.0 (C3_Ph, C5_Ph), 132.0 (C2_Ph, C6_Ph, C5_T), 140.2

(C1_Ba), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0

(C6_Pu); ESI MS: 530 (M⁺); Anal. calcd. for C₂₅H₂₄BrN₉: C,

56.61; H, 4.56; Found: C, 55.05; H, 4.50.

Benzyl-{7-[1-(4-methoxy-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-piperidine-1-yl-7H-purin-6-yl}-amine

(12b)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 11’. It was obtained as a white

solid with 80% Yield; mp: 148–149 °C; ¹H NMR

(400 MHz, CDCl₃): δ 8.60 (s, 1H_8Pu), 7.70 (s, 1H_5T), 7.20

(d, 1H_2Ph, 1H_6Ph), 7.10–7.00 (m, 5H_Ba), 6.80 (d, 1H_3Ph

,

Benzyl-{7-[1-(4-iodo-phenyl)-1H-[1,2,3]triazol-4-

ylmethyl]-2-pyrrolidin-1-yl-7H-purin-6-yl}-amine

(12e)

1H_5Ph), 5.50 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T), 3.50 (s,

3H_OCH3), 2.65 (m, 2H2_CH2pi), 2H3_CH2pi, 2H4_CH2pi), 1.80

(m, 2H₁, 2H_5(CH2Pi)); ¹³C (100 MHz, CDCl₃): 25.0 (C2,

C3, C4_(CH2pi)), 50.3 (C1, C5_(CH2pi)), 50.5_(CH2T)), 56.0_(OCH3)

,

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 11’. It was obtained as a white solid

58.5_(CH2Ba), 110.0 (C3_Ph, C5_Ph), 120.0 (C1_Ph), 126.5

(C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph), 128.0 (C3_Ba, C5_Ba,

C5_Pu), 132.0 (C2_Ph, C5_T), 140.2 (C1_Ba), 145.0 (C8_Pu),

155.2 (C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu), 162.0 (C4_Ph);

ESI MS: 469 (M⁺); Anal. calcd. for C₂₅H₂₆N₉O: C, 64.08;

H, 5.59; Found: C, 63.93; H, 5.14.

1

with 77% Yield; mp: 150.0–153 °C; H NMR (400 MHz,

CDCl₃): δ 8.70 (s, 1H_8Pu), 8.50 (s, 1H_5T), 7.65 (d, 1H_3Ph

,

1H_5Ph, J = 6.4 Hz), 7.30 (d, 1H_2Ph, 1H_6Ph, J = 4.8 Hz),

7.10–7.00 (m, 5H_Ba), 5.90 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T),

2.80 (m, 2H2_CH2py, 2H3_CH2py), 2.00 (m, 2H₂, 2H_3(CH2Py));

¹³C (100 MHz, CDCl₃): 23.0 (C2, C3_(CH2py)), 50.3 (C1,

C4_(CH2py)), 50.5_(CH2T)), 58.5_(CH2Ba), 100 (C4_Ph), 126.5

(C_4Ba), 127.0 (C2_Ba, C6_Ba, C1_Ph), 128.0 (C3_Ba, C5_Ba, C5_Pu),

130.0 (C3_Ph, C5_Ph), 132.0 (C2_Ph, C6_Ph, C5_T), 140.2 (C1_Ba),

145.0 (C8_Pu), 155.2 (C2_Pu), 155.3 (C4_Pu), 158.0 (C6_Pu); ESI

MS: 578 (M⁺); Anal. calcd. for C₂₅H₂₄IN₉: C, 52.00; H,

4.19; Found: C, 51.65; H, 4.00.

Benzyl-{2-pyrrolidin-1-yl-7-[1-(4-triﬂuoromethyl-

phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-7H-purin-6-yl}-

amine (12c)

This compound was prepared according to the procedure

given in the section ‘General reaction procedure for

synthesis of compound 11’. It was obtained as a white solid

1

with 75% Yield; mp: 155–156 °C; H NMR (400 MHz,

CDCl₃): δ 8.60 (s, 1H_8Pu), 7.70 (s, 1H_5T), 7.40 (d, 1H_3Ph

,

Cell culture and growth conditions

1H_5Ph, J = 7.8 Hz), 7.20 (d, 1H_2Ph, 1H_6Ph, J = 6.8 Hz),

7.10–7.00 (m, 5H_Ba), 5.50 (s, 2H_CH2Ba), 4.60 (s, 2H_CH2T),

2.75(m, 2H2_CH2py), 2H3_CH2py), 1.80 (m, 2H₂, 2H_3(CH2Py));

¹³C (100 MHz, CDCl₃): 23.0 (C2, C3_(CH2pi)), 50.3 (C1,

C4_(CH2pi)), 50.5_(CH2T)), 58.5_(CH2Ba), 114.0 (CF₃), 125.0

(C3_Ph, C5_Ph), 126.5 (C_4Ba), 127.0 (C2_Ba, C6_Ba, C6_Ph), 128.0

(C3_Ba, C5_Ba, C5_Pu), 129.0 (C6_Ph, C2_Ph),132.0 (C1_Ph, C4_Ph,

C5_T), 140.2 (C1_Ba), 145.0 (C8_Pu), 155.2 (C2_Pu), 155.3

A panel of human cancer cell lines—HCT-116 (colon),

HT-29 (colon), MCF-7 (breast), prostate (PC-3), SF-268

(CNS)—were procured from U.S. National Cancer Insti-

tute (NCI). Cell lines were grown in tissue culture ﬂasks in

complete growth medium (RPMI-1640) supplemented

with 10% fetal bovine serum, 100 μg/ml streptomycin and

100 units/ml penicillin in carbon dioxide incubator (New

Medicinal Chemistry Research

Brunswick, Galaxy 170 R, Eppendorf) at 37 °C, 5% CO2

and 98% RH.

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For cytotoxicity evaluation, cell suspension of optimum cell

density was seeded in 96-well ﬂat-bottom plates (NUNC).

Cell lines were seeded at respective inoculation densities per

well as HCT-116 (7500), HT-29 (7500), MCF-7 (8000),

Prostate (7500), SF-268 (10,000). One-hundred microlitres

of cell suspension was plated. The cells were then exposed to

different concentrations of test materials containing complete

growth medium for 24 h. The plates were again incubated

under the same conditions for another 48 h at 37 °C. Further,

cells were ﬁxed with ice cold TCA (trichloroacetic acid) for

1 h at 4 °C. After 1 h, the plates were rinsed three times with

water and allowed to air dry. After drying, 100 μl of 0.4%

SRB dye was added for half an hour at room temperature.

Plates were then washed three times with 1% vol/vol acetic

acid to remove the unbound SRB. After drying at room

temperature, the bound dye was solublized by adding 100 μl

of 10 mM TRIS (tris (hydroxymethyl)aminomethane) buffer

(pH-10.4) to each well. The plates were kept on the shaker

for 5 min to solublize the protein bound dye. Finally, optical

density (OD) was taken at 540 nm in a microplate reader

(Thermo Scientiﬁc). IC50 was determined by plotting OD

against concentration using graph pad prism software.

Acknowledgements We thank University of Pretoria for providing

postdoctoral fellowship to JK.

Rosemeyer H (2004) The chemo diversity of purine as a constituent of

natural products. Chem Biodivers 1:361–401

Compliance with ethical standards

Saman MV, Salim KY, Danter WR, Koropatnick J (2018) PLoS ONE

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Schellens JHM, Talbot DC (2005) Clinical trial designs. J Clin

Oncol 23:2060–2060

Conﬂict of interest The authors declare that they have no conﬂict of

interest.

Publisher’s note Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional afﬁliations.

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Article Doi

Synthesis and anticancer activity of N-9- and N-7- substituted 1,2,3 triazole analogues of 2,6-di-substituted purine

DOI: 10.1007/s00044-019-02456-9

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Article abstract of DOI:10.1007/s00044-019-02456-9

Full text of DOI:10.1007/s00044-019-02456-9

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