Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity

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Medicinal Chemistry Research ISSN 1054-2523 Med Chem ResDOI 10.1007/s00044-014-1142-6

Synthesis and biological evaluation of novelphenanthridinyl piperazine triazoles viaclick chemistry as anti-proliferative agents

Hunsur Nagendra Nagesh, Narva Suresh,Gollapalli Venkata Subrahmanya BhanuPrakash, Samarth Gupta, JanapalaVenkateswara Rao, et al.

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ORIGINAL RESEARCH

Synthesis and biological evaluation of novel phenanthridinylpiperazine triazoles via click chemistry as anti-proliferative agents

Hunsur Nagendra Nagesh • Narva Suresh • Gollapalli Venkata Subrahmanya Bhanu Prakash •

Samarth Gupta • Janapala Venkateswara Rao •

Kondapalli Venkata Gowri Chandra Sekhar

Received: 14 October 2013 / Accepted: 30 June 2014

� Springer Science+Business Media New York 2014

Abstract The preliminary results describe synthesis of a

series of novel 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)

piperazin-1-yl)phenanthridine analogs using hybrid

approach employing copper(I)-catalyzed azide-alkyne

cycloaddition and their evaluation as antiproliferative agents

against four cancer cell lines by MTT assay. Among the

synthesized compounds, 7g and 7h showed good activ-

ity against all the test cell lines. In particular, 7g

(IC50 = 9.73 ± 4.09 lM) exhibited excellent activity

against THP1 cancer cell line, and 7h (IC50 = 7.22 ±

0.32 lM) emerged as more active compound than the stan-

dard drug etoposide against HL60 cancer cell line.

Keywords Phenanthridine � Piperazine �Antiproliferative activity � Click chemistry �Microwave synthesis

Introduction

Cancer has become the major cause of death in both

developed and developing countries with the changes in the

living habitat of people and environment (Huang et al.,

2012). About 30 % of cancer deaths are due to the five

leading behavioral and dietary risks: high body mass index,

low fruit and vegetable intake, lack of physical activity,

tobacco and alcohol use. Deaths from cancer worldwide are

projected to continue rising, with an estimated 13.1 million

deaths in 2030 (WHO factsheets, 2013). Furthermore,

multidrug resistance of cancer cells is a major cause for the

failure of anti-cancer chemotherapy. It has been recognised

that multidrug resistance is multifactorial and that various

cellular pathways might be simultaneously involved in the

clinical drug resistance of cancer patients. Also, one of the

mechanisms that might be clinically active in cancer

patients is the prevention of the intracellular accumulation

of anticancer drugs by the expression of transport proteins

that pump drugs out of cells (Filipits, 2004). Cancer is

treated with surgery, radiation, chemotherapy, hormone

therapy, biological therapy, and targeted therapy. Chemo-

therapy is one of the promising methods in cancer treat-

ment. Combination chemotherapy is currently a standard

tool in the treatment of many cancers and has contributed

to increasing survival and cure rates (National Cancer

Institute, Cancer advances in focus 2010). Nevertheless, to

surmount the consequences emerging from multidrug

resistance of cancer cells, it is need of the hour to identify

novel molecules with unique therapeutic features.

1,2,3-Triazoles being imperative and proficient phar-

macophore, have occupied chief role not only in organic

chemistry but also in medicinal chemistry due to their ease

of synthesis by click chemistry with striking chemothera-

peutic features covering broad spectrum of biological

activities (Kolb and Sharpless, 2003; Agalave et al., 2011;

Rostovtsev et al., 2002). In particular, carboxyamidotriaz-

ole (Fig. 1) is an anticancer drug, containing triazole

moiety with potential antineoplastic activity. 1,2,3-triazole

H. N. Nagesh � N. Suresh � S. Gupta � K. V. G. C. Sekhar (&)

Department of Chemistry, Birla Institute of Technology &

Science-Pilani, Hyderabad Campus, Jawahar Nagar, Shamirpet

Mandal, Hyderabad 500 078, Telangana, India

e-mail: [email protected]; [email protected]

G. V. S. B. Prakash � J. V. Rao

Biology Division, Indian Institute of Chemical Technology,

Hyderabad 500 607, Telangana, India

G. V. S. B. Prakash

Collaborative Drug Discovery Research (CDDR) Lab, Faculty

of Pharmacy, Universiti Teknologi MARA (UiTM), 42300

Bandar Puncak Alam, Selangor, Darul Ehsan, Malaysia

123

Med Chem Res

DOI 10.1007/s00044-014-1142-6

MEDICINALCHEMISTRYRESEARCH

Author's personal copy

ring serves two purposes: (a) it facilitates stronger cap

group interactions with the amino acid side chains at the

entrance of the histone deacetylase active site; (b) it also

serves as bioisostere to the pharmacokinetically and toxi-

cologically disadvantageous groups such as amide and

ketone (Chen et al., 2008; Kumbhare et al., 2012). The

insertion of 1,2,3-triazole ring which led to the synthesis of

N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-

phenyloxazole-4-carboxamide is found to be more potent

with an IC50 of 46 nM against MCF-7 cancer cell line

compared to the compounds which lack 1,2,3-triazole

moiety (Stefely et al., 2010).

On the other hand, quinoline skeleton acquired signifi-

cant interests, owing to their niche in the drug discovery

arena. Quinoline derivatives are known to exhibit broad

biological spectrum such as anticancer (Metwally et al.,

2013), antimalarial, antibacterial (Rudrapal et al., 2013),

anti-HIV-1 (Rizvi et al., 2013), antiprotozoal (Opsenica

et al., 2013), and antimycobacterial (Mathew et al., 2013).

Anticancer drugs with quinoline backbone prevailing in the

market dofequidar and TAS-103 are depicted in Fig. 2.

Quinoline compounds are identified to possess anticancer

property by intercalation or alkylation of deoxyribonucleic

acid. Targeting this pathway was found to be unsuccessful

as the compounds lack selectivity and exhibit broad spec-

trum of activity. However, it was justified that the selec-

tivity was greatly dependent on the appropriate substituent

at the 2nd position of quinoline (Atwell et al., 1988). Also,

currently available drugs in the market lack selectivity

against normal and tumor cells. Consequently, worsening

the treatment of primary or secondary resistance mecha-

nisms evolved in the cancer cells (O’Connor, 2009). Some

of the quinoline and 1,2,3-triazole-containing molecules

which exhibit anticancer activity are depicted in Fig. 3.

Makhey et al., synthesized 2,3,8,9-tetramethoxy-5-

methylbenzo[i]phenanthridine (XX) which exhibited IC50

of 22 and 11 lM against the growth of RPMI 8402 and

CPT-K5 cell lines, respectively (Makhey et al., 2003).

Tseng et al., synthesized indeno[1,2-c]quinoline deriva-

tives (XY) appended with piperazine at 6th position which

turned out to be most potent with GI50 values of 0.52, 0.74,

6.76, and 0.64 lM against the growth of HeLa, SKHep,

AGS, and A549 cells, respectively (Tseng et al., 2008).

Kumbhare et al., synthesized 2-(2-((1-(3-(trifluoro-

methyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl) benzo

[d]thiazole (XZ) and reported IC50 of 11 lM in colon

cancer cells (Kumbhare et al., 2012). Inspired by the bio-

logical importance of 1,2,3-triazoles and quinoline as

anticancer agents, we chalked out a trajectory to incorpo-

rate these two active pharmacophores. This impelled us to

design new chemical entities emphasizing hybrid approach

(Fig. 4) anticipating attractive drug scaffold features with

important therapeutic potential. Hence, highlighting the

importance of substituent at 2nd position of quinoline, we

coupled 6-(4-(prop-2-ynyl)piperazin-1-yl)phenanthridine

with aryl and aryl sulfonyl azides and wanted to explore the

synergistic effect of these heterocycles toward anticancer

activity. Altogether, we report phenanthridinyl piperazine

triazoles as novel antiproliferative agents for the first time.

The synthetic route to achieve title compounds is depicted

in Scheme 1.

Results and discussion

To generate a novel template which could serve as effec-

tive ligand for antiproliferative activity, we adopted

reported procedure (Badger et al., 1951; Meseroll et al.,

2011) with slight modification starting from 9-fluorenone

(1) to prepare 6-Chlorophenanthridine (4), then 6-(pipera-

zin-1-yl) phenanthridine (5) was synthesized by treating 4

with anhydrous piperazine in DMF under microwave

irradiation at 150 �C for 20 min using Biotage initiator

with a pre-stirring of 30 s and stirring rate at 600 rpm.

Compound 6 was obtained by heating 5 with propargyl

bromide (80 % in toluene) in the presence of triethylamine

(TEA) using N,N-dimethylformamide (DMF) as solvent.

The title compounds were synthesized from 6 by means of

copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)

employing catalytic amount of CuSO4�5H2O and sodium

ascorbate in 1:2 ratio of water and tert-butanol to get

desired regioselective 1,4-substituted triazole compounds

7a–f. While catalytic amount of copper (I)-thiophene-2-

carboxylate (CuTC) and toluene as solvent was used to

synthesize the regioselective 1,4-substituted triazole com-

pounds 7g–h. The 1H NMR spectrum of all title com-

pounds displayed multiplet in the range of 2.75–2.95 ppm

and 3.45–3.65 ppm corresponding to piperazine (–CH2–)

protons, singlet in the range of 3.85–4.00 ppm

Fig. 1 Structure of anticancer drug carboxyamidotriazole

Fig. 2 Structure of anticancer drugs with quinoline backbone:

a Dofequidar b TAS-103

Med Chem Res

123


https://www.researchgate.net/publication/5454564_Oyelere_Synthesis_and_structure-activity_relationship_of_histone_deacetylase_HDAC_inhibitors_with_triazole-linked_cap_group?el=1_x_8&enrichId=rgreq-d6c8bba5-386f-47a5-b3f8-c98694fed5db&enrichSource=Y292ZXJQYWdlOzI2NDM5NzE2MTtBUzoxNzMxNTM2MzIzOTkzNjBAMTQxODI5NDQ1MTUxMg==

https://www.researchgate.net/publication/257320453_Synthesis_antimalarial-_and_antibacterial_activity_evaluation_of_some_new_4-aminoquinoline_derivatives?el=1_x_8&enrichId=rgreq-d6c8bba5-386f-47a5-b3f8-c98694fed5db&enrichSource=Y292ZXJQYWdlOzI2NDM5NzE2MTtBUzoxNzMxNTM2MzIzOTkzNjBAMTQxODI5NDQ1MTUxMg==

https://www.researchgate.net/publication/42540617_N-1-Benzyl-1H-123-triazol-4-ylmethylarylamide_as_a_New_Scaffold_that_Provides_Rapid_Access_to_Antimicrotubule_Agents_Synthesis_and_Evaluation_of_Antiproliferative_Activity_Against_Select_Cancer_Cell_L?el=1_x_8&enrichId=rgreq-d6c8bba5-386f-47a5-b3f8-c98694fed5db&enrichSource=Y292ZXJQYWdlOzI2NDM5NzE2MTtBUzoxNzMxNTM2MzIzOTkzNjBAMTQxODI5NDQ1MTUxMg==

https://www.researchgate.net/publication/5670518_Synthesis_and_antiproliferative_evaluation_of_certain_indeno12-cquinoline_derivatives?el=1_x_8&enrichId=rgreq-d6c8bba5-386f-47a5-b3f8-c98694fed5db&enrichSource=Y292ZXJQYWdlOzI2NDM5NzE2MTtBUzoxNzMxNTM2MzIzOTkzNjBAMTQxODI5NDQ1MTUxMg==

corresponding to methylene proton, and proton of 1,2,3-

triazole ring resonated in the range of 7.8-8.2 ppm. Both

analytical and spectral data (1H NMR, 13C NMR, HRMS,

and elemental analysis) of all the synthesized compounds

were confirmed and employed further for their evaluation

in antiproliferative activity.

Anti-proliferative activity

All the synthesized compounds were evaluated for their

antiproliferative activity against four cancer cell lines such

as THP1 (Human acute monocytic leukemia), Colo205

(human colon carcinoma), U937 (human leukemic

monocytic lymphoma), and HL60 (Human promyelocytic

leukemia cells) at concentrations between 1 and 200 lM

using Etoposide and N,N-dimethylsulfoxide (DMSO) as

positive- and negative-control, respectively. The anti-pro-

liferative activity results are summarized in Table 1.

It is evident from the results that considerable structure–

activity relationship could be drawn for the tested com-

pounds. Substituents at 2nd or 3rd position of phenyl ring

could not able to arrest the cancer cell growth against all the

test cell lines (7b–e). Moderate activity was noticed against

HL60 cancer cell line when we introduced methylene linker

between triazole and aryl ring (7a, IC50 = 112.72 ±

7.96 lM). However, compound 7f exhibited good activity

(IC50 = 23.01 ± 2.36 lM) on Colo 205 and significant

Fig. 3 Some of the quinoline and 1,2,3-triazole-containing molecules which exhibit anticancer activity

Fig. 4 Design strategy to

achieve title compounds

Med Chem Res

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activity (IC50 = 198.85 ± 31.59 lM) on HL60 cancer cell

lines when appended with the methoxy group at 4th position

of phenyl ring. With this encouraging result in hand, we

sandwiched sulfonyl group between triazole and aryl ring to

fetch compounds 7g and 7h. These derivatives have shown

significant decrease in cell viability against all the test cell

lines on concentration dependent manner (Table 1). Among

the test cell lines, 7g exhibited excellent activity against

HL60, THP1, and Colo205 cancer cell lines with IC50

of 17.69 ± 1.30, 9.73 ± 4.09, and 18.55 ± 2.471 lM,

respectively, followed by moderate activity against U937

cancer cell line with IC50 = 68.65 ± 6.46 lM. While 7h

exhibited good activity against Colo205 and THP1 cell lines

with IC50 = 17.51 ± 3.47 and 11.27 ± 0.86 lM, respec-

tively, followed by moderate activity against U937 cell line

with IC50 = 40.07 ± 3.12 lM. It is noteworthy that com-

pound 7h emerged as promising anticancer agent against

HL60 cancer line with IC50 = 7.22 ± 0.32 lM indicating

more active than the positive control etoposide.

Experimental

Chemistry

Chemicals and solvents were procured from commercial

sources and are analytically pure. Thin-layer chromatog-

raphy (TLC) was carried out on aluminum-supported silica

gel plates (Merck 60 F254) with visualization of compo-

nents by UV light (254 nm). Column chromatography was

carried out on silica gel (Merck 230–400 mesh). 1H NMR

spectra and 13C NMR spectra were recorded at 300 or

400 MHz using a Bruker AV 400 spectrometer (Bruker

CO., Switzerland) in CDCl3 or DMSO-d6 solution with

tetramethylsilane as the internal standard, and chemical

shift values (d) were given in ppm. Microwave reactions

were performed in closed vessel using Biotage Initiator

microwave synthesizer (Uppsala, Sweden). Melting points

were determined on an electro thermal melting point

apparatus (Stuart-SMP30) in open capillary tubes and are

uncorrected. High-resolution mass spectra (HRMS) were

recorded on QSTAR XL Hybrid MS/MS mass spectrom-

eter. Elemental analysis was carried out on Elementar

(vario MICRO cube, Hanau, Germany).

9-fluorenone oxime (2)

In a 3:1 mixture of 60 mL ethanol and 20 mL water,

9-fluorenone (0.055 mol) was refluxed with hydroxylamine

hydrochloride (0.111 mol) and sodium acetate (0.111 mol)

for 1.5 h. The volatile was evaporated, and the residue was

filtered. The obtained solid was recrystallized from mini-

mum amount of ethanol to yield 9-fluorenone oxime.

Yield: 91 %. mp 207–209 �C. 1H NMR (400 MHz,

DMSO-d6) d 12.58 (1H, s, NH), 8.35 (1H, d, H4), 7.81 (2H,

m, H-1 H-7), 7.72 (1H, d, H-6), 7.48 (1H, t, H-8), 7.33 (3H,

m, H-2, H-3, H-9). 13C NMR (100 MHz, DMSO-d6) d163.2 (C-5), 139.9 (C-10), 138.2 (C-11), 132.8 (C-12),

131.8 (C-13), 128.8 (C-2), 128.3 (C-8), 127.2 (C-4), 126.7

(C-6), 124.1 (C-3), 123.5 (C-7), 120.9 (C-1), 118.3 (C-9).

6- (5H) -phenanthridinone (3)

9-Fluorenone oxime (0.0512 mol) was heated with stirring

in PPA (0.512 mol) and P2O5 (0.0256 mol). The acid

became much less viscous and was easily stirred. Once the

temperature of the mixture reached 160 �C, it was main-

tained at 150 �C for 30 min. Over the course of heating, the

oxime dissolved and the mixture became dark brown-

orange. Following heating, the mixture was maintained at

room temperature without stirring for 15 h. The cool

mixture was then warmed slightly so the viscous acidic

mixture could be poured over 3 inches of ice in a 600 mL

beaker. After stirring several minutes, the dark tarry

material began to solidify, and a pale tan precipitate was

liberated. The precipitate was washed several times with

water and collected by vacuum filtration to give 6-(5H)-

phenanthridinone. Yield = 94 %; off white solid, mp

289–290 �C; 1H NMR (400 MHz, DMSO-d6) d 11.69 (1H,

bs, NH), 8.52 (1H, d, J = 8.0 Hz, H-7), 8.40 (1H, d,

J = 8.0 Hz, H-4), 8.33 (1H, dd, J = 8.0, 1.0 Hz, H-10),

7.86 (1H, m, H-9), 7.65 (1H, m, H-7), 7.50 (1H, m, H-8),

7.37 (1H, dd, J = 8.0, 1.0 Hz, H-3), 7.27 (1H, m, H-2). 13C

NMR (100 MHz, DMSO-d6) d 161.3 (C-6), 137.0 (C-12),

134.7 (C-13), 133.3 (C-14), 133.0 (C-9), 128.4 (C-7), 128.0

(C-10), 126.2 (C-1), 123.7 (C-3), 123.1 (C-8), 122.7 (C-2),

118.0 (C-11), 116.6 (C-4).

6-chlorophenanthridine (4)

Phenanthridinone (0.0512 mol) was solubilised in phos-

phorus oxychloride (0.512 mol) in the presence of N,N-

dimethylaniline (0.0256 mol), and the mixture was heated

at reflux for 3 h. The solvent was removed under reduced

pressure and the residue poured into ice and the product

was extracted using CH2Cl2 (4 9 20 mL). The organic

layers were washed using an aqueous solution of K2CO3

(0.1 M, 2 9 20 mL), dried over sodium sulfate, filtered,

and the solvent was removed in vacuo. The product was

recrystallized twice from ethanol–water, to yield 6-chlor-

ophenanthridine. Yield = 72 %; beige crystals, mp

111–112 �C; 1H NMR (300 MHz, CDCl3): d 8.65 (1H, d,

J = 8.4 Hz, H-1); 8.57 (1H, d, J = 8.1 Hz, H-7); 8.52 (1H,

d, J = 8.1 Hz, H-4); 8.12 (1H, d, J = 7.6 Hz, H-10); 7.94

(1H, t, J = 7.2 Hz, H-2), 7.82-7.71 (3H, m, H-3, H-9,

H-8). 13C NMR (75.4 MHz, CDCl3): d 149.7 (C-6); 131.8

Med Chem Res

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(C-12), 130.8 (C-13), 130.3 (C-3), 130.0 (C-9), 128.9 (C-

1), 127.8 (C-7), 126.9 (C-4), 125.4 (C-8), 123.9 (C-2),

122.8 (C-14), 118.9 (C-11).

Synthesis of 6-(piperazin-1-yl)phenanthridine (5)

6-chlorophenanthridine (2.34 mmol) was dissolved in

DMF (5 mL) in an oven dry microwave vial. Then

TEA (3.51 mmol) followed by anhydrous piperazine

(4.68 mmol) were added. Microwave vial was sealed with

aluminum cap, and the resultant mixture was subjected to

microwave irradiation at 150 �C for 20 min. Completion of

the reaction was monitored by TLC using 10 % MeOH in

DCM as mobile phase. After the reaction was complete,

DMF was evaporated under vacuo and added 5 mL of

water. Compound was extracted using EtOAc (3 9 5 mL).

Combined organic layers were washed with saturated brine

solution, dried over anhydrous sodium sulfate, and evap-

orated in vacuo. Column chromatography of the residue

using gradient 5 % MeOH in DCM gave 6-(piperazin-

1-yl)phenanthridine. Yield = 62 %; yellow solid,

m.p.116–119 �C; 1H NMR (CDCl3, 400 MHz) d 8.57 (1H,

d, J = 8.2 Hz, H-4 phenanthridine), 8.45 (1H, d,

J = 7.9 Hz, H-7 phenanthridine), 8.16 (1H, d, J = 8.3 Hz,

H-10 phenanthridine), 7.87 (1H, d, J = 7.5 Hz, H-1 phe-

nanthridine), 7.79 (1H, t, J = 7.6 Hz, H-9 phenanthridine),

7.63 (2H, t, J = 7.6 Hz H-3, H-8 phenanthridine), 7.49

(1H, t, J = 7.6 Hz, H-2 phenanthridine), 4.81 (1H, s, br,

piperazine NH), 3.82–3.25 (8H, m, CH2 piperazine). 13C

NMR (CDCl3, 100.61 MHz) d 171.87 (C-6 phenanthri-

dine), 147.68 (C-12 phenanthridine), 136.79 (C-13 phe-

nanthridine), 134.12 (C-3 phenanthridine), 129.97 (C-9

phenanthridine), 128.32 (C-1 phenanthridine), 126.11 (C-7


phenanthridine), 122.86 (C-10 phenanthridine), 121.64 (C-

2 phenanthridine), 120.76 (C-11 phenanthridine), 113.78

(C-14 phenanthridine), 51.23 (C-2, C-6 piperazine), 46.69

(C-3, C-5 piperazine). HRMS: (ESI m/z) for C17H18N3

calcd: 264.1501, found: 264.1513 (M?H)?. Anal. Calcu-

lated for C17H18N3: C 77.24, H 6.86, N15.90; found: C

77.11, H 6.35, N 15.43.

Synthesis of 6-(4-(prop-2-ynyl)piperazin-1-yl)phenan-

thridine (6): 6-(piperazin-1-yl)phenanthridine (0.0187 mol)

was dissolved in DMF (50 mL), then TEA (0.0280 mol)

followed by propargyl bromide (80 % in toluene)

(0.0280 mmol) were added. Resultant mixture was heated

at 70 �C for 1.5 h. Completion of the reaction was moni-

tored by TLC using 5 % MeOH in DCM as mobile phase.

After the reaction was complete, DMF was evaporated in

vacuo and added 50 mL of water. Compound was extracted

using EtOAc (3 9 15 mL). Combined organic layers were

washed with saturated brine solution, dried over anhydrous

sodium sulfate, and evaporated in vacuo. Column chro-

matography of the residue using 1–2 % MeOH in DCM

gave 6-(4-(prop-2-ynyl)piperazin-1-yl)phenanthridine.

Yield = 92 %; pale yellow solid, m.p. 125–126 �C; 1H

NMR (CDCl3, 400 MHz) d 8.46 (1H, d, J = 8.0 Hz, H-4

phenanthridine), 8.36 (1H, d, J = 7.6 Hz, H-7 phenan-

thridine), 8.21 (1H, d, J = 7.2 Hz, H-10 phenanthridine),

7.92 (1H, d, J = 9.6 Hz, H-1 phenanthridine), 7.76–7.39

(m, 4H), 3.94 (2H, s, propargyl CH2), 3.58 (4H, m, CH2

piperazine), 2.92 (4H, m, CH2 piperazine), 2.42 (1H, s,

alkyne proton). 13C NMR (CDCl3, 100.61 MHz) d 174.27

(C-6 phenanthridine), 138.62 (C-12 phenanthridine),

134.53 (C-13 phenanthridine), 131.65 (C-3 phenanthri-

dine), 129.44 (C-9 phenanthridine), 128.33 (C-1 phenan-

thridine), 127.45 (C-7 phenanthridine), 125.34 (C-4




78.64 (C-2 propargyl), 76.89 (C-1 propargyl), 58.72

(C-2, C-6 piperazine), 56.21 (C-3, C-5 piperazine), 50.63

Table 1 Anti-proliferative activity of phenanthridinyl triazole derivatives against different cancerous cell lines THP1, Colo205, U937, and

HL60

Compound ID R THP1 COLO205 U937 HL60

IC50 (lM)

7a PhCH2 – – – 112.72 ± 7.96

7b 2-ClPh – – – –

7c 3-ClPh – – – –

7d 3-CF3Ph – – – –

7e 3-OMePh – – – –

7f 4-OMePh – 23.01 ± 2.36 – 198.85 ± 31.59

7g Ph 9.73 ± 4.09 18.55 ± 2.47 68.65 ± 6.46 17.69 ± 1.30

7h 4-MePh 11.27 ± 0.86 17.51 ± 3.47 40.07 ± 3.12 7.22 ± 0.32

Etoposide 3.76 ± 0.17 10.62 ± 0.41 10.26 ± 0.20 14.10 ± 0.54

– indicates not active at 200 lM

Med Chem Res

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(CH2 propargyl). HRMS: (ESI m/z) for C20H20N3 calcd:

302.1657, found: 302.1633 (M?H)?. Anal. Calculated for

C20H20N3: C 79.44, H 6.67, N 13.90; found: C 79.58, H

6.12, N 13.82.

Synthesis of 6-(4-((substituted-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7a–f)

6-(4-(prop-2-ynyl)piperazin-1-yl)phenanthridine (0.6571 mmol)

was dissolved in 1:2 ratio of water and t-BuOH (3 mL).

Then CuSO4.5H2O (0.1314 mmol), sodium ascorbate

(0.1314 mmol), and aryl azides (0.7228 mmol) was added.

Resultant mixture was stirred at RT for 3 h. Completion of

the reaction was monitored by TLC using 2 % MeOH in

DCM as mobile phase. After the reaction was complete,

volatiles were evaporated in vacuo, and the compound

was extracted using EtOAc (3 9 5 mL). Combined organic

layers were washed with saturated brine solution, dried over

anhydrous sodium sulfate, and evaporated in vacuo. Column

chromatography of the residue using 1–2 % MeOH in DCM

gave regioselective 1,4-substituted title compounds.

6-(4-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-

yl)phenanthridine (7a)

White solid (91 %), m.p. 132–133 8C; 1H NMR (CDCl3,

400 MHz) d 8.55 (1H, d, J = 8.4 Hz, H-4 phenanthridine),

8.43 (1H, d, J = 7.2 Hz, H-7 phenanthridine), 8.12 (1H, d,

J = 7.6 Hz, H-10 phenanthridine), 8.00 (1H, s, triazole

C–H), 7.88 (1H, d, J = 9.2 Hz, H-1 phenanthridine),

7.78–7.32 (9H, m), 4.98 (2H, s, CH2Ph), 3.92 (2H, s, CH2

triazole), 3.55 (4H, m, CH2 piperazine), 2.90 (4H, m, CH2

piperazine). 13C NMR (CDCl3, 100.61 MHz) d 172.46 (C-


(C-13, phenanthridine), 139.84 (C-1 Bn), 138.32 (C-9, C-3

phenanthridine), 135.51 (C-4 triazole), 134.42 (C-2 Bn),

130.80 (C-6 Bn), 129.47 (C-7 phenanthridine), 128.13 (C-3

Bn), 127.69 (C-5 Bn), 126.61 (C-5 triazole), 124.60 (C-1

phenanthridine), 123.11 (C-2, phenanthridine), 122.24 (C-4



(C-14 phenanthridine), 60.16 (Bn CH2), 58.18 (CH2 tria-

zole), 50.74 (C-2, C-6 piperazine), 45.27 (C-3, C-5 piper-

azine). HRMS: (ESI m/z) for C27H27N6 calculated:


C27H27N6: C 74.46, H 6.25, N 19.30; found: C 74.93, H

6.79, N 19.11.

6-(4-((1-(2-chlorophenyl)-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7b)

Pale yellow solid (82 %); m.p. 122–1238C; 1H NMR

(CDCl3, 400 MHz) d 8.35 (1H, d, J = 8.4 Hz, H-4 phe-

nanthridine), 8.22 (1H, d, J = 7.6, Hz, H-7 phenanthri-

dine), 8.19 (1H, d, J = 7.6 Hz, H-10 phenanthridine), 8.00

(1H, s, triazole C–H), 7.96 (1H, d, J = 9.2 Hz, H-1 phe-

nanthridine), 7.74 (1H, d, J = 7.2 Hz, H-3 2-ClPh), 7.68

(1H, d, J = 9.2 Hz, H-6 2-ClPh), 7.58–7.36 (6H, m), 3.92

(2H, s, CH2 triazole), 3.55 (4H, m, CH2 piperazine), 2.90

(4H, m, CH2 piperazine). 13C NMR (CDCl3, 100.61 MHz)

d 173.42 (C-6 phenanthridine), 149.76 (C-12 phenanthri-

dine), 142.36 (C-2 2-ClPh), 140.58 (C-13 phenanthridine),

139.84 (C-9 phenanthridine), 137.84 (C-3 phenanthridine),

Scheme 1 Synthetic route to achieve title compounds. Reagents and

conditions: (i) NH2OH.HCl (2equiv), NaOAc (2equiv), EtOH:H2O

(3:1), reflux 1.5 h (ii) PPA (10 equiv), P2O5 (0.5equiv), heating at

150 �C, 0.5 h (iii) POCl3 (10equiv), N,N-dimethylaniline (0.5equiv),

reflux 3 h (iv) anhydrous piperazine (3equiv), Et3N (1.5equiv), DMF,

MW, 150 �C, 20 min (v) propargyl bromide (80 % in toluene)

(1.2equiv), Et3N (1.5equiv), DMF, heating at 70 �C 1.5 h (vi)

substituted azides, CuSO4�5H2O (10 mol%), sodium ascorbate

(10 mol %), H2O:t-BuOH (1:2), RT 3 h (vii) substituted sulfonyl

azides, CuTC (10 mol %), toluene, RT, 1 h

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135.51 (C-4 triazole), 130.80 (C-1 2-ClPh), 129.47 (C-4

2-ClPh), 128.42 (C-7 phenanthridine), 128.13 (C-1 phe-

nanthridine), 127.92 (C-6 2-ClPh), 127.69 (C-3 2-ClPh),

126.61 (C-5 triazole), 125.60 (C-8 phenanthridine), 124.72


121.64 (C-5 2-ClPh), 120.43 (C-2 phenanthridine), 119.92


58.18 (CH2 triazole), 50.74 (C-2, C-6 piperazine), 45.27

(C-3, C-5 piperazine). HRMS: (ESI m/z) for C26H24ClN6

calculated: 455.1751, found: 455.1758 (M?H)?. Anal.

Calculated for C26H24ClN6: C 68.49, H 5.31, N 18.43;

found: C 67.93, H 5.09, N 18.67.

6-(4-((1-(3-chlorophenyl)-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7c)

White solid (94 %); m.p. 121–122 8C; 1H NMR (CDCl3,




C–H), 7.93 (1H, d, J = 9.2 Hz, H-1 phenanthridine), 7.84

(1H, d, J = 7.2 Hz, H-2 3-ClPh), 7.81 (1H, d, J = 7.6 Hz,

H-4 3-ClPh), 7.78–7.46 (6H, m), 3.92 (2H, s, CH2 triazole),

3.55 (4H, m, CH2 piperazine), 2.90 (4H, m, CH2 pipera-

zine). 13C NMR (CDCl3, 100.61 MHz) d 173.12 (C-6


13 phenanthridine), 142.58 (C-3 3-ClPh), 139.84 (C-9


triazole), 130.80 (C-5 3-ClPh), 129.47 (C-1 3-ClPh),

128.13 (C-7 phenanthridine), 127.69 (C-1 phenanthridine),

126.61 (C-5 triazole), 125.60 (C-4 3-ClPh), 124.12 (C-6




nanthridine), 116.36 (C-14 phenanthridine), 58.18 (CH2

triazole), 50.74 (C-2, C-6 piperazine), 45.27 (C-3, C-5

piperazine). HRMS: (ESI m/z) for C26H24ClN6 calculated:


C26H24ClN6: C 68.49, H 5.31, N 18.43; found: C 68.31, H

5.37, N 18.11.

6-(4-((1-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7d)

Yellow solid (85 %); m.p. 130–131 8C; 1H NMR (CDCl3,



J = 7.6 Hz, H-10 phenanthridine), 8.09 (1H, s, triazole C–

H), 7.98 (1H, d, J = 9.6 Hz, H-1 phenanthridine), 7.94

(1H, d, J = 7.2 Hz, H-2 3-CF3Ph), 7.86 (1H, d, J = 7.6 Hz

H-4 3-CF3Ph), 7.76–7.39 (m, 6H), 3.92 (2H, s, CH2 tria-

zole), 3.55 (4H, m, CH2 piperazine), 2.90 (4H, m, CH2

piperazine). 13C NMR (CDCl3, 100.61 MHz) d 173.93


143.45 (C-13 phenanthridine), 142.58 (C-6 3-CF3Ph),

138.44 (C-3 3-CF3Ph), 137.84 (C-9 phenanthridine),


(CF3), 128.13 (C-5 3-CF3Ph), 127.69 (C-7 phenanthridine),






116.76 (C-14 phenanthridine), 58.78 (CH2 triazole), 50.64

(C-2, C-6 piperazine), 45.36 (C-3, C-5 piperazine). HRMS:

(ESI m/z) for C27H24F3N6 calculated: 489.2015, found:

489.2008 (M?H)?. Anal. Calculated for C27H24F3N6: C

66.25, H 4.94, N 17.17; found: C 66.77, H 4.26, N 17.87.

6-(4-((1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7e)

Pale yellow semi solid (68 %); m.p. oily mass; 1H NMR


nanthridine), 8.36 (1H, d, J = 7.6 Hz, H-7 phenanthri-




dine), 7.76–7.39 (5H, m), 6.96 (1H, d, J = 7.6 Hz, H-4

3-OMePh), 6.92 (1H, s, H-2 3-OMePh), 3.99 (3H, s,

OCH3), 3.94 (2H, s, CH2 triazole), 3.58 (4H, m, CH2

piperazine), 2.92 (4H, m, CH2 piperazine). 13C NMR

(CDCl3, 100.61 MHz) d 174.27 (C-6 phenanthridine),


dine), 141.28 (C-3 3-OMePh), 138.62 (C-9 phenanthri-

dine), 136.45 (C-3 phenanthridine), 134.53 (C-4 triazole),

131.65 (C-5 3-OMePh), 129.44 (C-7 phenanthridine),

128.33 (C-1 phenanthridine), 127.45 (C-1 3-OMePh),



122.64 (C-2 phenanthridine), 121.32 (C-6 3-OMePh),



58.72 (OCH3), 56.21(CH2 triazole), 50.63 (C-2, C-6

piperazine), 45.38 (C-3, C-5 piperazine). HRMS: (ESI

m/z) for C27H27N6O calculated: 451.2246, found: 451.2252

(M?H)?. Anal. Calculated for C27H27N6O: C 71.82, H

6.03, N 18.61; found: C 71.07, H 6.35, N 18.17.

6-(4-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7f)

Pale green solid (78 %); m.p. 128–129 8C; 1H NMR




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nanthridine), 7.83 (2H, d, J = 7.6 Hz, H-2, H-6 4-OMePh),

7.68–7.37 (4H, m), 6.92 (2H, d, J = 7.2 Hz, H-3, H-5

4-OMePh), 3.98 (3H, s, OCH3), 3.92 (2H, s, CH2 triazole),

3.58 (4H, m, CH2 piperazine), 2.93 (4H, m, CH2 pipera-

zine). 13C NMR (CDCl3, 100.61 MHz) d 174.10 (C-6

phenanthridine), 162.42 (C-4 OMePh), 149.72 (C-12 phe-



triazole), 134.80 (C-2, C-6 OMePh), 129.47 (C-7 phenan-

thridine), 128.13 (C-1 phenanthridine), 127.69 (C-8 phe-

nanthridine), 126.61 (C-5 triazole), 125.60 (C-4


2 phenanthridine), 121.12 (C-1, OMePh), 119.62 (C-11

phenanthridine), 118.45 (C-14 phenanthridine), 115.46

(C-3, OMePh), 62.34 (OCH3), 58.98 (CH2 triazole), 51.74

(C-2, C-6 piperazine), 46.27 (C-3, C-5 piperazine). HRMS:

(ESI m/z) for C27H27N6O calculated: 451.2246, found:

451.2250 (M?H)?. Anal. Calculated for C27H27N6O: C

71.82, H 6.03, N 18.61; found: C 71.67, H 5.94, N 18.61.

Synthesis of 6-(4-((substituted-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7g, 7h)

6-(4-(prop-2-ynyl)piperazin-1-yl)phenanthridine (0.6571 mmol)

was dissolved in toluene (5 mL). Then CuTC (0.0657 mmol)

and sulfonylazides (0.7228 mmol) was added. Resultant

mixture was stirred at RT for 1 h. Completion of the

reaction was monitored by TLC using 2 % MeOH in DCM

as mobile phase. After the reaction was complete, saturated

aq. NH4Cl (5 mL) was added and the compound was

extracted using EtOAc (3 9 5 mL). Combined organic

layers were washed with saturated brine solution, dried

over anhydrous sodium sulfate, and evaporated in vacuo.

Column chromatography of the residue using 1–2 %

MeOH in DCM gave regioselective 1,4-substituted title

compounds.

6-(4-((1-benzenesulfonyl-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine (7g)





C–H), 7.93 (1H, d, J = 9.2 Hz, H-1 phenanthridine),

7.78–7.32 (9H, m), 3.92 (2H, s, CH2 triazole), 3.54 (4H, m,

CH2 piperazine), 2.90 (4H, m, CH2 piperazine). 13C NMR

(CDCl3, 100.61 MHz) d 174.12 (C-6 phenanthridine),


dine), 139.84 (C-1 SO2Ph), 137.84 (C-4 SO2Ph), 135.51

(C-4 triazole), 134.42 (C-9 phenanthridine), 130.80 (C-3

phenanthridine), 129.47 (C-3, C-5 SO2Ph), 128.13 (C-2,

C-6 SO2Ph), 127.69 (C-7 phenanthridine), 126.61 (C-1

phenanthridine), 124.60 (C-5 triazole), 123.11 (C-8 phe-


phenanthridine), 119.92 (C-2 phenanthridine), 114.85


58.18 (CH2 triazole), 50.74 (C-2, C-6 piperazine), 45.27

(C-3, C-5 piperazine). HRMS: (ESI m/z) for C26H25N6O2S

calculated: 485.1760, found: 485.1764 (M?H)?. Anal.

Calculated for C26H25N6O2S: C 64.31, H 5.19, N 17.31, S

6.60; found: C 64.92, H 4.89, N 17.12, S 6.19.

6-(4-((1-tosyl-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-

yl)phenanthridine (7h)




J = 7.6 Hz, H-10 phenanthridine), 8.00 (1H, s, triazole C–

H), 7.93 (1H, d, J = 9.2 Hz, H-1 phenanthridine), 7.83

(2H, d, J = 9.2 Hz, H-2, H-6 4-MePh), 7.72 (2H, d,

J = 7.6 Hz, H-3, H-5 4-OMePh), 7.68–7.46 (4H, m), 3.92

(2H, s, CH2 triazole), 3.55 (4H, m, CH2 piperazine), 2.90

(4H, m, CH2 piperazine), 2.42 (3H, s, –CH3 4-CH3Ph). 13C

NMR (CDCl3, 100.61 MHz) d 172.12 (C-6 phenanthri-

dine), 150.76 (C-12 phenanthridine), 142.35 (C-13 phe-

nanthridine), 140.58 (C-1 4-MePhSO2), 139.84 (C-4

4-MePhSO2), 138.84 (C-9 phenanthridine), 135.51 (C-4

triazole), 134.80 (C-3 phenanthridine), 129.47 (C-3, C-5

4-MePhSO2), 128.13 (C-7 phenanthridine), 127.69 (C-1


triazole), 123.11 (C-2, C-6 4-MePhSO2), 121.64 (C-4



(C-14 phenanthridine), 58.18 (CH2 triazole), 50.74 (C-2,

C-6 piperazine), 45.27 (C-3, C-5 piperazine), 24.64 (CH3

4-MePhSO2). HRMS: (ESI m/z) for C27H27N6O2S calcu-

lated: 499.1916, found: 499.1922 (M?H)?.Anal. Calcu-

lated for C27H27N6O2S: C 64.91, H 5.45, N 16.82, S 6.42;

found: C 65.12, H 5.75, N 16.72, S 6.26.

Cell lines and cell culture

The cell lines THP1 (Human acute monocytic leukemia),

Colo205 (human colon carcinoma), U937 (human leuke-

mic monocytic lymphoma), and HL60 (Human promye-

locytic leukemia cells) were obtained from the National

Centre for Cellular Sciences (NCCS), Pune, India. Cells

were cultured in RPMI-1640 media, supplemented with

10 % heat-inactivated fetal bovine serum (FBS), 100 units/

mL penicillin and 100 lg/mL streptomycin. All cell lines

were maintained in culture at 37 �C in an atmosphere of

5 % CO2.

Med Chem Res

123


Cytotoxicity

Cell proliferation or viability was measured using the MTT

[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium

bromide] assay (Mosmann, 1983). Cells were seeded in

each well containing 100 lL medium at a final density of

2 9 104cells/well, in 96-well micro titer plates at identical

conditions. Substituted triazole compounds were dissolved

and eventually further diluted in dimethylsulfoxide

(DMSO). After overnight incubation, the cells were treated

with different test concentrations (1–200 lM) or carrier

solvent alone in a final volume of 200 lL with five repli-

cates each. The concentration of DMSO did not exceed

0.1 %, which is considered non-toxic to cells. After 24 h,

10 lL of MTT (5 mg/mL) was added to each well, and the

plate was incubated at 37 �C in the dark for 4 h. Super-

natants were removed, and the formazan crystals were

solubilised in DMSO (100 lL/well) for 30 min at room

temperature. The reduction of MTT was quantified by

absorbance at 570 nm in a spectrophotometer (Spectra

MAX Plus; Molecular Devices; supported by SOFTmax

PRO-5.0). Effects of the test compounds on cell viability

were calculated using cells treated with DMSO as control.

The data were subjected to linear regression analysis, and

the regression lines were plotted for the best straight-line

fit. The IC50 (inhibition of cell viability) concentrations

were calculated using the respective regression equations.

Conclusion

A series of eight 6-(4-((substituted-1H-1,2,3-triazol-4-

yl)methyl)piperazin-1-yl)phenanthridine analogs were

synthesized by employing environmentally benign CuAAC

and evaluated for their anti-proliferative activity in differ-

ent types of cell lines (THP1, Colo205, U937 & HL60).

The differential activity among the cell lines may be

accounted to the substituent attached to nitrogen atom of

1,2,3-triazole ring. Influxion of sulfonyl functional group

led to the discovery of 7h, which emerged as more potent

than the positive control etoposide with IC50 = 7.22 ±

0.32 lM against HL60 cancer cell line. These encouraging

results promote us to further explore by structural modifi-

cation on these derivatives which could lead to promising

anticancer agents. For the first time we report phenanth-

ridinyl piperazine as new heterocyclic moiety with anti-

cancer property. This study opens up researchers to exploit

this heterocycle for lead optimisation and further devel-

opment of novel anticancer agents.

Acknowledgments The financial assistance provided by Depart-

ment of Science & Technology (under Fast Track scheme: SR/FT/CS-

076/2009), New Delhi, India is gratefully acknowledged. One of the

authors, NS thanks UGC, New Delhi for the award of research

fellowship.

Conflict of interest The authors declare no conflict of interest.

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Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity

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