DESIGN, SYNTHESIS AND ANTICANCER ACTIVITIES OF NOVEL UNSATURATED FATTY ACID-BASED b-HYDROXY 1,2,3-TRIAZOLES

DESIGN, SYNTHESIS AND ANTICANCER ACTIVITIES OF NOVEL UNSATURATED FATTY ACID-BASED b-HYDROXY 1,2,3-TRIAZOLES

Vijay Manneganti ¹, Lakshmi Anu Prabhavathi Devi Bethala *¹, Badari Narayana Prasad Rachapudi ¹, Ashita Singh ², Ramesh Ummanni ²

Centre for Lipid Research ¹, Chemical Biology ², Indian Institute of Chemical Technology, Hyderabad - 500 007, Andhra Pradesh, India

ABSTRACT: A series of novel unsaturated fatty acid based b-hydroxy 1,2,3-triazole hybrids were designed and synthesised in excellent yields by esterification, epoxidation of oleic, ricinoleic  and 10-undecenoic acids followed by azidolysis and “click” reaction with different alkynes. All the b-hydroxy 1,2,3-triazole hybrids were characterised by ESI-MS, IR and NMR spectra as well as HRMS analysis and were screened in vitro for their anticancer activity against selected four human cancer cell lines (DU-145, HeLa, MCF-7 and A549) in comparison with  doxorubicin, a standard anticancer drug. Among all the triazoles, methyl oleate with-CH₂OH as 1,2,3-triazole side chain (1dii) exhibited good anti cancer activity against DU-145, HeLa, MCF-7 and A549 human cancer cell lines with IC₅₀ values 10.73, 13.61, 11.93, and 16.54 μM respectively.

Fatty acid, Epoxidation,

Azidolysis, Click reaction,

b-Hydroxy 1,2,3-Triazole,

Cytotoxic activity

INTRODUCTION: Amongst the pharmacologically active nitrogenous compounds, 1,2,3-triazoles and their derivatives attracted considerable attention for the past few decades due to their chemotherapeutical value. 1,2,3-Triazole moiety is stable to metabolic degradation and capable of hydrogen bonding, which could be favourable in binding of bio-molecular targets and increasing solubility ¹. Moreover, 1,2,3-triazoles are attractive linker units which could connect two pharmacophores to give an innovative bi-functional drugs, have become increasingly useful and important in constructing bioactive molecules and functional molecules.

Copper (I) has recently been found to be an efficient and regio specific catalyst for the preparation of 1,4-disubstituted 1,2,3-triazole derivatives ². This reaction has found application in various facets of drug discovery as it enables a modular approach to generate novel pharmacophores utilizing a collection of reliable chemical reactions. 1,2,3-Triazoles have found widespread applications in chemical synthesis, drug discovery ³, organometallic chemistry ⁴, surface science ⁵ and nanochemistry ⁶. In addition, a number of compounds containing 1,2,3-triazoles have shown a broad spectrum of biological activities such as antimicrobial ⁷, antitubercular ⁸, anti-HIV ⁹, analgesic ¹⁰, anticancer activity ¹¹ etc.

Cancer is one of the life-threatening diseases worldwide from decades and its chemotherapy has entered a new era of molecularly targeted therapeutics, which is highly selective and not associated with the serious toxicities of conventional cytotoxic drugs. There is a pressing need for new anticancer agents with high potency, less toxicity in non-cancerous cells, and unique targets of action. Currently, cancer therapy interfering with a single biological molecule or pathway has been successfully utilized for the treatment in clinics ¹².

There is general belief that agents modulating more than one target could have superior efficacy compared to single target drugs ¹³. Therefore, modulating multiple targets simultaneously can be achieved by the combination of multiple drugs with different mechanisms or by single chemical entity that could modulate several targets of a multi factorial disease. As a result, there is increasing interest in the discovery of agents that concomitantly address more than one biological target for cancer treatment.

Fatty acids are ubiquitous in nature and as such they belong to a physiologically important class of molecule involved in cell energy storage (e.g. adipose tissues), membrane structure (phospholipid bilayer) and in various signalling pathways. A number of azido, diazido and iodo-azido long chain fatty esters have been synthesized and the physical and biological properties of such unusual lipid molecules have been studied ¹⁴. Azides are good starting blocks for organic molecules to be converted into nitrogen heterocycles by decomposition or addition reactions ¹⁵. In the present study, we report the synthesis of oleic, ricinoleic and 10-undecnoic acid based b-hydroxy1,2,3-triazole derivatives for the first time by epoxidation and azidolysis of fatty acids followed by “click” reaction with aliphatic and aromatic alkynes. All the b-hydroxy 1,2,3-triazole derivatives were characterised by ESI-MS, IR and NMR spectra as well as HRMS analysis and further screened for anticancer activity against four human cancer cell lines namely, DU-145, HeLa, MCF-7 and A549 in comparison with  a standard anticancer drug doxorubicin.

MATERIALS AND METHODS:

All chemicals (reagents and solvents) were procured from S. D. Fine or Sigma Aldrich Chemical companies unless otherwise indicated. Progress of the reactions was monitored by using TLC plates (coated with TLC grade silica gel, obtained from Merck, India). The spots were located by exposure to iodine vapours or under UV- light. Column chromatography was performed over silica gel (100-200 mesh) procured from Qualigens (India) using freshly distilled solvents. Melting points were determined in open capillaries on Barnstead Electro thermal’s melting point apparatus (India) and are uncorrected. IR spectra were recorded on a Perkin Elmer (model: spectrum BX) FT-IR Spectrometer using CHCl₃ and KBr.

Nuclear magnetic resonance (¹H NMR and ¹³C NMR) spectra were recorded at 300 K Brucker UXNMR (operating at 300 MHz and 500 for ¹H and 75 MHz for ¹³C NMR) in CDCl₃ as solvents with TMS as an internal standard. Chemical shifts (δ) are given in ppm and coupling constants (J) in Hz. The splitting pattern abbreviations are as follows: s, singlet; bs, broad singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet. Mass spectra were recorded using Waters, Micromass-Quatromicro electron spray ionization (ESI-MS). All of the compounds were drawn using the program CS Chem Draw Ultra version 10.0.

General Procedure:

Synthesis of fatty acid methyl ester ¹⁵ (1a/2a/3a): A stirred solution of fatty acid (5 g) in 2% H₂SO₄/CH₃OH (50 mL) was refluxed for 4 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with water till the water washings become neutral to pH and dried over anhydrous Na₂SO_4. The residue obtained after removing the solvent in rotary evaporator under reduced pressure was purified by column chromatography (100% hexane) to afford pure fatty acid methyl ester.

Synthesis of fatty acid methyl ester epoxides ¹⁶ (1b/2b/3b):

A mixture of fatty acid methyl ester and m-CPBA (1:1.5) in DCM (20 mL) was stirred at room temperature for 4 h. The reaction mixture was washed with saturated solutions of NaHSO₃ followed by NaHCO₃ and NaCl. The organic layer was dried over anhydrous Na₂SO₄ and the solvent was evaporated under reduced pressure. The residue obtained was further purified by silica gel column chromatography (EtOAc/Hexane) to afford pure product.

Synthesis of β-hydroxy azide derivatives of fatty acid methyl ester ¹⁷ (1c/2c/3c):

A mixture of epoxide (1 eq), NaN₃ (5 eq) and NH₄Cl (2.3 eq) in MeOH:H₂O (8:1) was heated to reflux for 12 h. Methanol from the reaction mixture was removed under reduced pressure, the residue obtained was washed with brine solution and dried over anhydrous Na₂SO₄. The product was further purified by silica gel column chromatography (EtOAc / Hexane).

Synthesis of β-hydroxy-(4-aryl/alkyl-1H-1,2,3-triazol-1-yl) derivatives of fatty acid methyl esters ² (1d_(i-v)/2d_(i-v)/3d_(i-v)):          CuSO₄.5H₂O (0.01eq), sodium ascorbate (0.1eq) were added to a stirred suspension of fatty acid azidohydrin (1eq) and alkyne (1eq) in t-BuOH:H₂O (1:1) and heated to reflux for 6 h. Progress of the reaction was monitored by TLC. After the reaction was completed solvent was removed under reduced pressure and the product was extracted in to EtOAc. The organic layer was washed with brine solution, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get crude 1,2,3-triazole. The product was further purified by silica gel column chromatography (EtOAc /Hexane/CHCl₃).

Synthesis of β-hydroxy-(4-alkyl/aryl-1H-1,2,3-triazol-1-yl) derivatives of fatty acids ^18,19 (1e_(i-v)/2e_(i-v)/3e_(i-v)):

10% aq. KOH was added to 1,2,3-triazole derivatives of fatty acid methyl esters and stirred at 90 °C for 4 h. After the reaction was completed the reaction mixture was neutralized with dil. HCl and the pure product was extracted into ethyl acetate. Organic layer was washed with brine solution, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get pure compound.

 TABLE 1: PHYSICO CHEMICAL PROPERTIES OF COMPOUNDS (1a/2a/3a)

          * [M]⁺ from ESI-MS data.

TABLE 2: SPECTRAL DATA OF SYNTHESIZED COMPOUNDS (1a/2a/3a)

 TABLE 3: PHYSICO CHEMICAL PROPERTIES OF COMPOUNDS (1b/2b/3b)

           * [M+H]⁺ from ESI-MS data.

TABLE 4: SPECTRAL DATA OF SYNTHESIZED COMPOUNDS (1b/2b/3b)

TABLE 5: PHYSICO CHEMICAL PROPERTIES OF COMPOUNDS (1c/2c/3c)

                 ^* Nomenclature as reported in reference ¹⁷

                 ^** [M+Na]⁺ from ESI-MS data.

TABLE 6: SPECTRAL DATA OF SYNTHESIZED COMPOUNDS (1c/2c/3c)

TABLE 7: PHYSICO CHEMICAL PROPERTIES OF OLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 1(d-e)_(i-v)

 TABLE 8: PHYSICO CHEMICAL PROPERTIES OF RICINOLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 2(d-e)_(i-v)

TABLE 9: PHYSICO CHEMICAL PROPERTIES OF 10-UNDECENOLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 3(d-e)_(i-v)

 TABLE 10: IR, MASS AND HRMS SPECTRAL DATA OF OLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 1(d-e)_(i-v)

               ^† [M]⁺, ^* [M+H]⁺

 TABLE 11: IR, MASS AND HRMS SPECTRAL DATA OF RICINOLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 2(d-e)_(i-v)

               ^† [M]⁺, ^* [M+H]⁺, ^$ [M-H]⁺

 TABLE 12: IR, MASS AND HRMS SPECTRAL DATA OF RICINOLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 3(d-e)_(i-v)

                ^† [M]⁺, ^* [M+H]⁺, ^$ [M-H]⁺, ^# [M+Na]⁺

TABLE 13: ¹H AND ¹³C NMR DATA OF OLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 1(d-e)_(i-v)

 TABLE 14: ¹H AND ¹³C NMR DATA OF RICINOLEIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 2(d-e)_(i-v)

 TABLE 15: ¹H AND ¹³C NMR DATA OF 10-UNDECENOIC ACID BASED b-HYDROXY 1,2,3-TRIAZOLES 3(d-e)_(i-v)

 Pharmacology:

Cytotoxicity Evaluation: Cellular viability was determined using an MTT-micro cultured tetrazolium assay as reported previously ²⁰, with minor modifications. Briefly, all four selected cell lines were seeded in 96-well plates with flat bottom surface (10,000 cells/well in 100 µl of culture medium containing 10% serum) and cultured for 18–24 h with a constant supply of 5% CO₂ in a humid incubator. The series of compounds synthesized are dissolved in DMSO to prepare stock concentrations from 0.5 to 5000 µM with 10 fold increase in the range. From working stock two µl of test compounds and doxorubicin (as a standard control anticancer drug prepared in DMSO) were added to the culture media to achieve a final concentration of 0-100 µm final concentration to the cells.

Cells continued to grow further for 48 h with a constant supply of 5% CO₂ in the humid incubator. On termination of assay, filter-sterilized 3-(4, 5-dimethylthiazol-2-yl) - 2, 5 - diphenyltetrazolium bromide (MTT) in PBS (5 mg/ml, 10 ml per well) was added to the culture plate. After 2 h of further incubation subsequently the medium was removed and 100 ml of DMSO was added to the cells solubilising MTT bound to cells. The absorbance of purple colour directly proportional to cell growth was measured at 562nm in a multimode micro plate reader (Tecan GENios; Tecan AG, Mannedorf, Switzerland). The IC₅₀ values were calculated from the observed cell growth with and without the test compounds. The results analyzed are from three independent experiments, each performed in triplicates.

 RESULTS AND DISCUSSION:

Chemistry:

The β-hydroxy 1,2,3-triazole hybrids of unsaturated fatty acids namely, oleic (1), ricinoleic (2) and 10-undecnoic acid (3) were synthesised as shown in Figures 1 and 2. The employed synthetic protocol comprises of i) esterification, ii) epoxidation, iii) azidolysis, iv) “click” reaction followed by v) hydrolysis. According to Figure 1, the fatty acids 1/2/3 were converted to methyl esters 1a/2a/3a by treating with 2% H₂SO₄/MeOH ¹⁵ then subjected to epoxidation with m-CPBA in DCM ¹⁶ to obtain corresponding epoxy fatty acid methyl esters 1b/2b/3b in 85, 70 and 85% yield respectively.

Nucleophilic ring opening of 1b/2b/3b with NaN₃ in presence of NH₄Cl in aq. MeOH resulting in the corresponding regio and stereo isomeric mixture ¹⁷ of β-hydroxy azides 1c/2c/3c in 85, 90 and 95% yields.

FIGURE 1: REAGENTS AND CONDITIONS: i) 2% H₂SO₄/CH₃OH, REFLUX. ii) m-CPBA, DCM, ROOM TEMPERATURE. iii) NaN₃, NH₄Cl, MeOH: H₂O (8:1), REFLUX.

The main focus of the present work is to impart value addition to the fatty acids, hence the mixture of β-hydroxy azides itself have been chosen as azide source for click reaction. All the above synthesized compounds were characterized by physico chemical, analytical and spectral data and are in comparison with the reported authentic samples as depicted in Tables 1-9. Presence of sharp peaks in FT-IR spectrum of 1c/2c/3c at 2100-2010 cm^-1 and broad peaks 3350-3480 cm^-1 corresponding to the -N₃ and -OH functional groups respectively are characteristic of β-hydroxy azide. These azides 1c/2c/3c were subjected to

click reaction with different alkynes namely, oct-1-yne (i), prop-2-yn-1-ol (ii), phenyl acetylene (iii), 3-ethynylphenol (iv) and 2-ethynyl-6-methoxy naphthalene (v) in presence of CuSO₄.5H₂O and sodium ascorbate ² as reducing agent in 1:1 (v/v) mixture of t-butanol:water to obtain corresponding β-hydroxy1,2,3-triazole fatty acid methyl esters 1d_(i-v)/2d_(i-v)/3d_(i-v) in good yields. The fatty acid methyl ester triazoles on further hydrolysis with aq. KOH ^18,19 at 90 °C to obtain corresponding β-hydroxy1,2,3-triazole fatty acids 1e_(i-v)/2e_(i-v)/3e_(i-v) in quantitative yields as depicted in Figure 2.

FIGURE 2: REAGENTS AND CONDITIONS: a) ALKYNES (i-v), t-BuOH:H₂O (1:1), CuSO₄. 5H₂O, SOD ASCORBATE, REFLUX. b) 10% aq. KOH, 90 °C.

All the purified structure hybrids of 1, 2 and 3 were fully characterized by IR, Mass, HRMS (Tables 10-12) and ¹H and ¹³C NMR (Tables 13-15) spectral studies. ¹H NMR spectrum of 1d_iii shows peaks at δ 7.20-7.39 corresponding to aromatic protons of phenyl ring and singlet at δ 7.98 corresponding to the proton of 1,2,3-triazole ring and -OCH₃ peak as singlet at δ 3.60; the characteristic peaks for methyl ester. The prominent peaks in the ¹³C NMR for the carbonyl and methoxy carbons of 1d_iii, were found to be at δ 174.2, and 51.4 respectively, including requisite number of carbons. Absence of peaks at δ 51.4 and δ 3.60 of ¹³C & ¹H NMRs of compound 1e_iii clearly indicate the complete hydrolysis of methyl ester to acid. The molecular ion peaks in ESI-MS spectrum of 1d_iii and 1e_iii were found to be at 458 [M+H]⁺ and 443 [M]⁺ respectively, were in good coincidence with HRMS values as shown in Tables 10-12.

 TABLE 16: INHIBITORY RESULTS OF FATTY ACID BASED Β-HYDROXY 1,2,3-TRIAZOLE HYBRIDS AGAINST FOUR HUMAN CANCER CELL LINES

^* Inhibitory activity was assayed by exposure to substance and expressed as concentration required to inhibit tumour cell proliferation by 50% (IC₅₀). Data are presented as the mean ± SDs of three independent experiments.

In the ¹H and ¹³C NMR spectral data of oleic and 10-undecenoic acid based triazoles no additional peaks corresponding to the isomeric mixture was observed, while that of ricinoleic acid based triazoles two more additional peaks than the expected according to the molecular structure were noticed and were found to be characteristic peaks for C₉, C₁₀ regio isomers formed by the nucleophilic ring opening of epoxide with azide nucleophile as reported in the literature ⁴².  In case of ricinoleic acid based triazoles, C₁₂-OH functionality of carbon chain directs major isomer by the attack of N₃^¯ through less hindered side of epoxide ring resulting in the formation of unequal proportions of regio isomers.

The reason for the non appearance of the additional peaks in oleic acid derivatives might be the formation of approximately equal ratios of the regio isomeric mixture and in 10-undecenoic acid, nucleophilic ring opening at the terminal carbon of the epoxide ring leads to the formation of major percentage of terminal azide containing β-hydroxy azide.

 Anticancer Activity: The IC₅₀ values (concentration required to inhibit tumour cell proliferation by 50%) for the synthesized β-hydroxy1,2,3-triazole compounds i.e., 1d_(i-v)/2d_(i-v)/3d_(i-v) and 1e_(i-v)/2e_(i-v)/3e_(i-v) against four human cancer cell lines namely, DU-145 (human prostate cancer cell line), HeLa (human cervical cancer cell line), MCF-7 (human breast cancer cell line) and A549 (human lung cancer cell line) were determined in MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay based on the conversion of MTT into formazan crystals by living cells. The IC₅₀ values were listed in Table 16 and the standard anticancer drug doxorubicin was used as positive control.

Among the oleic acid based triazole compounds (1d_(i-v) and 1e_(i-v)) only methyl oleate triazole 1d_ii with -CH₂OH side chain exhibited good anti cancer activity against the above four human cancer cell lines with IC₅₀ values 10.73, 13.61, 11.93, and 16.54 μM, respectively. Whereas, it’s hydrolyzed compound i.e. 1e_ii didn’t show any activity. However, the methyl oleate triazole 1d_iii with phenyl side chain showed poor activity, where as its acid 1e_iii exhibited moderate activity against DU-145 and MCF-7 with IC₅₀ values 17.96 and 19.19 μM respectively. In case of methyl oleate triazole 1d_iv with hydroxyl phenyl side chain the IC₅₀ values were found to be 19.01 and 16.45 μM against DU-145 and HeLa cell lines, and its acid derivative 1e_iv exhibited moderate activity against HeLa (IC₅₀ value 19.48 μM) cancer cell line only.

The cytotoxicity study of the ricinoleic acid based β-hydroxy 1,2,3-triazoles (2d_(i-v) and 2e_(i-v)) revealed that, only 2d_i with hexyl side chain in methyl ester form and 2e_v with 6-methoxynaphthyl side chain in acid form were found to be moderately active against MCF-7 (IC₅₀ value 24.08 μM) and DU-145 (IC₅₀ value 24.02 μM) respectively. The triazole compounds 2e_ii, 2e_iv with -CH₂OH, m-OH-Ph as side chain in acid form and 2d_v with 6-OMe-naphthyl side chain in ester form are inactive against all the cell lines and remaining triazoles showed poor activity.

In case of 10-undecenoic acid based triazoles (3d_(i-v) and 3e_(i-v)), only 3e_i with hexyl side chain in acid form was found to be active against DU-145 cancer cell line (IC₅₀ value 21.67 μM). The compounds 3d_ii, 3d_v with -CH₂OH, 6-OMe-naphthyl side chain in ester form and 3e_iii, 3e_iv, 3e_v with phenyl, m-OH-Ph, 6-OMe-naphthyl side chain in acid form are inactive against all the cell lines and the remaining triazoles were not considerably active.

CONCLUSIONS: In conclusion, a new class of fatty acid based β-hydroxy 1,2,3-triazole hybrids namely, oleic, ricinoleic and 10-undecenoic acid based were synthesized for the first time and screened for anticancer activity against four human cancer call lines. The key step in this protocol is the 1, 3-dipolar addition of β-hydroxy azide of fatty acids with different alkyl/aryl alkynes using click reaction.

Among all the synthesized 1,2,3-triazole derivatives (1-3d_(i-v) & 1-3e_(i-v)), only methyl oleate based triazoles exhibited promising to moderate anti cancer activity against four human cancer cell lines DU-145, HeLa, MCF-7 and A549. Methyl oleate triazole with -CH₂OH side chain 1d_ii exhibited promising anti cancer activity against the above four human cancer cell lines with IC₅₀ values

10.73, 13.61, 11.93 and 16.54 μM respectively. Moderate activity was observed for the methyl oleate triazole with m-OH-Ph side chain 1d_iv showing IC₅₀ values 19.01, 16.45, 20.85 and 20.05 μM against the above cell lines, where as its acid form is active against only HeLa (IC₅₀ value 19.49 μM), A549 (IC₅₀ value 24.16 μM) cell lines. Whereas, oleic acid triazole with phenyl side chain 1e_iii is active against DU-145 and MCF-7 cell lines only with IC₅₀ values 17.96 and 19.19 μM respectively.

ACKNOWLEDGEMENTS: The authors acknowledge the financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi, India, in the form of Senior Research Fellowships (SRF) to M. Vijay and Open Source Drug discovery (OSDD) to Ashita Singh.

REFERENCES:

1. Vatmurge NS, Hazra BG, Pore VS, Shirazi F, Chavan PS and Deshpande MV: Synthesis and antimicrobial activity of β-lactam-bile acid conjugates linked via triazole. Bioorganic and Medicinal Chemistry Letters 2008; 18: 2043-2047.
2. Meldal M and Tornoe CW: Cu-catalyzed azide-alkyne cycloaddition. Chemical Review 2008; 108: 2952-3015.
3. Kolb HC and Sharpless KB: The growing impact of click chemistry on drug discovery, Drug Discovery. Today 2003; 8: 1128-1137.
4. Ganesh V, Sudhir VS, Kundu T and Chandrasekaran S: 10 Years of click chemistry: Synthesis and applications of ferrocene derived triazoles. Chemistry-An Asian Journal 2011; 6: 2670-2694.
5. Schulz M, Tanner S, Barqawi H and Binder WH: Macrocyclization of polymers via ring-closing metathesis and azide/alkyne-click-reactions: An approach to cyclic polyisobutylenes. Journal of Polymer Science Part A: Polymer Chemistry 2010; 48: 671-680.
6. Han J and Gao C: Functionalization of carbon nanotubes and other nanocarbons by azide chemistry. Nano Micro Letters 2010; 2: 213-226.
7. Wahab BFA, Latif EA, Mohamed HA and Awad GEA: Design and synthesis of new 4-pyrazolin-3-yl-1,2,3-triazoles and 1,2,3-triazol-4-yl-pyrazolin-1-ylthiazoles as potential antimicrobial agents. European Journal of Medicinal Chemistry 2012; 52: 263-268.
8. Menendez C, Chollet A, Rodriguez F, Inard C, Pascz MR, Lherbet C and Baltas M: Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents. European Journal of Medicinal Chemistry 2012; 52: 275-283.
9. Silva FC, Souza MCBVD, Frugulhetti IIP, Castro HC, Souza SLO, Souza TML, Rodrigues DQ, Souza AMT, Abreu PA, Passamani F, Rodrigues CR and Ferreira VF: Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates. European Journal of Medicinal Chemistry 2009; 44: 373-383.
10. Isloor AM, Kalluraya B, Rao M and Rahiman AM: Sydnone derivatives: Part - IV: Synthesis of 3-aryl-4-(3-substituted pyrazolidene hydrazino-4-thiazolyl) sydnones as possible analgesic and anticonvulsant agents. Journal of Saudi Chemical Society 2000; 4: 265-270.
11. Singh P, Raj R, Kumar V, Mahajan MP, Bedi PMS, Kaur T and Saxena AK: 1,2,3- Triazole tethered β-lactam-chalcone bifunctional hybrids: Synthesis and anticancer evaluation. European Journal of Medicinal Chemistry 2012; 47: 594-600.
12. Bode AM and Dong Z: Cancer prevention research-then and now. Nature Reviews Cancer 2009; 9: 508-516.
13. Zhan P and Liu XY: Designed multiple ligands: An emerging anti-HIV drug discovery paradigm. Current Pharmaceutical Design 2009; 15 (16): 1893-1917.
14. Jonathan AZ, Alberto N, Gary DS and Daniel KYS: Clickable Lipids: Azido and Alkynyl Fatty Acids and Triacylglycerols. Journal of American Oil Chemical Society 2009; 86: 1115-1121.
15. Shunsuke C: Application of Organic Azides for the Synthesis of Nitrogen-containing Molecules. Synlett 2012; 23: 21-44.x
16. Wu FL, Ross BP and McGeary RP: New methodology for the conversion of epoxides to alkenes. European Journal of Organic Chemistry 2010; 10: 1989-1998.
17. Furmeier S and Metzger JO: Fat-derived aziridines and their n-substituted derivatives: Biologically active compounds based on renewable raw materials. European Journal of Organic Chemistry 2003; 4: 649-659.
18. Champetier G and Despas M: The poly condensation of 11-amino-10-hydroxyundecanoic acid. Bulletin de la Societe Chimique de France 1955; 431-435.
19. Despas M: Preparation and study of the reaction of polycondensation of a hydroxy amino acid: 11-amino-10-hydroxyundecanoic acid. Annales de Chimie 1958; 13: 496-513.
20. Singh A, Mahipal B, Chandrasekhar S and Ummanni R: 5-epi-Torrubiellutin C shows antiproliferative activity on DU145 prostate cancer cells through inactivation of the AKT/mTOR pathway. Anticancer Drugs 2014; 25(4): 385-392.
    

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    How to cite this article:

    Manneganti V, Bethala LAPD, Rachapudi BNP, Singh A, Ummanni R: Design, Synthesis and Anticancer Activities of Novel Unsaturated Fatty Acid-Based b-Hydroxy 1,2,3-Triazoles. Int J Pharm Sci Res 2015; 6(4): 1635-49.doi: 10.13040/IJPSR.0975-8232.6(4).1635-49.

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