An Efficient and Alternative method for Synthesis of Nitroxoline

 

Rahul Uttamrao Devkar¹*, Durga Prasad Rao P², Kishore Gokavarapu¹, Shiva Rama Krishna Samala³

¹Production Department–Helios Lifesciences Limited, 79 and 100, Industrial Growth Center, Malanpur,

District: Bhind, MP–477117

²Quality Control Department–Helios Lifesciences Limited, 79 and 100, Industrial Growth Center, Malanpur, District: Bhind, MP–477117

³Research and Development Department–Helios Lifesciences Limited, 79 and 100, Industrial Growth Center, Malanpur, District: Bhind, MP–477117

*Corresponding Author E-mail: rahuldevkar1985@gmail.com

An efficient simple hazardous free process for the synthesis of Nitroxoline. This compoundcan be used as antibiotic drug, particularly effective for the treatment of urinary tract infections. Prepared intermediate and target compound characterized by ¹H-NMR and mass spectroscopy analysis.

Graphical abstract:

 

 

INTRODUCTION:

Nitroxoline (5-nitro-8-hydroxy-quinoline) is an established antibiotic that has been widely used in European, Asian and African countries for >50 years (1). It is particularly effective for the treatment of urinary tract infections (UTI) due to its unique pharmacokinetic properties(1). When administered orally, nitroxoline is rapidly absorbed into the plasma and then excreted into urine(2). It also has a long retention time in urine (2), thus, making it ideal for UTI treatment. Recently, nitroxoline has gained considerable attention due to its potent anticancer properties.

It was first identified as an effective inhibitor of angiogenesis by two parallel screens: A target-based screen for methionine aminopeptidase-2 (MetAP-2) inhibitors from a library of 175,000 chemical compounds and a cell-based screen using the Johns Hopkins Drug Library to identify currently used clinical drugs that can also inhibit human umbilical vein endothelial cell (HUVEC) proliferation (3). Thereafter, more studies confirmed the anticancer activity of nitroxoline and further demonstrated its anticancer mechanism (3–5). In particular, nitroxoline demonstrated potent anticancer activity against various types of cancer cell, including lymphoma, leukemia, glioma, bladder cancer, breast cancer, pancreatic cancer and ovarian cancer cells (3–5). As well as inhibiting angiogenesis, nitroxoline was also able to induce cancer cell apoptosis (4), and suppress cancer cell migration and invasion (6). Taken together, as an established drug for UTI treatment, nitroxoline has exhibited great promise as a novel candidate for anticancer treatment.

 

Drug repurposing, the process of identifying novel uses for existing drugs, has been gaining popularity in recent years. The major advantage of this approach is that the pharmacokinetic, pharmacodynamics and toxicity profiles of known drugs are generally well known due to of years of clinical history (1,7). Thus, exploring established non-cancer drugs for anticancer activity provides an opportunity to rapidly advance therapeutic strategies into clinical trials. To rapidly advance nitroxoline repurposing for anticancer treatment into clinical trials, the present study performed systemic preclinical pharmacodynamic evaluation of nitroxoline, with specific aims to confirm the anticancer activity of nitroxoline, select cancer types suitable for nitroxoline treatment and provide a reference dosage regimen for future clinical application.

 

Experimental section:

TLC was run on silica gel–G and visualization was done using iodine or UV light. NMR spectra were recorded on Varian Gemini 400 M Hz instrument using Tetramethylsilane as an internal standard in DMSO-d₆. Chemical shifts are expressed in ppm. Mass spectra were recorded on Agilent-LCMS instrument.

 

RESULTS AND DISCUSSION:

The synthesis of target compound prepared in two steps, obtained target compound purified by crystallization using DMF and water as solvent system.

 

8-Hydroxyquinoline (1) to yield 8-Hydroxy-5-Nitrosoquinoline (2) in the presence of sodium nitrite and sulfuric acid. Compound 2 treated with nitric acid in the presence of acetic acid produce the title compound (3), obtained target compound purified by crystallization method using DMF, water as solvents. Intermediate (2) and title Compound (3) were confirmed by spectral analysis like ¹H NMR and Mass analysis.

 

Chemistry:

8-Hydroxy-5-Nitrosoquinoline (2)

To a mixture of water and sulfuric acid (ration10:0.4 mol) charged 8-Hydroxyquinoline (1) (1mol) (8HQ) (1) at 15-20°C then cool to 10-15°Ccharged sodium nitrite aqueous solution drop wise in duration of 2-3hr, maintained 3hr checked HPLC absence of (1) then adjusted P^H=9 using aqueous sodium hydroxide solution maintained at same P^Haround30min, adjusted P^H=5 using acetic acid and obtained precipitated solid (compound 2) was filtered and dried, (yield 90%).¹H NMR (400 MHz, DMSO-d₆): 9.74 (brs, 1H), 8.95 (d, 1H), 8.41 (d, 1H), 8.17 (d, 1H), 7.6 (t, 1H) 7.04 (d, 1H). MS: m/z 175 [M+H] ⁺.

 

Nitroxoline (3):

To a mixture of 8-Hydroxy-5-Nitrosoquinoline (2) (1mol) and water (1:3 mol), charged nitric acid drop wise at 20-25°C maintained 3-4hr by HPLC found absence of compound 2, then charged DM water (5mol) adjusted P^H 7-8 using aqueous sodium hydroxide solution maintained around 30min then adjusted P^H=5 using acetic acid obtained solid (3) filtered and dried (yield 80%)¹H NMR (400 MHz, DMSO-d₆): 11.94 (brs, 1H), 9.1 (d, 1H), 8.99 (d, 1H), 8.33 (d, 1H), 7.76 (t, 1H) 6.77. MS: m/z 191 [M+H] ⁺.

 

Purification:

In 3 volume of methanol Nitroxoline crude (3) compound was charged heated 60-65°C observed clear solution then cool to 40-45°C obtained precipitated solid was filtered and dissolved in 3 volume of DMF to get clear solution then charged 5 volume of water to get solid, precipitated pure solid Nitroxoline compound (3) was filtered and dried under vacuum (Yield 70%, Purity by HPLC 99.5%).

 

CONCLUSION:

In summary, an efficient and novel procedure of Nitroxoline using 8-Hydroxyquinoline as starting material.

 

ACKNOWLEDGMENT:

We gratefully acknowledge the generous support provided by Helios Lifesciences Limited as a special project on Nitroxoline.

 

REFERENCES:

1.     Shim JS, Liu JO. Recent advances in drug repositioning for the discovery of new anticancer drugs. Int J Biol Sci. 2014; 10:654–663.

2.     Mrhar A, Kopitar Z, Kozjek F, Presl V, Karba R. Clinical pharmacokinetics of nitroxoline. Int J Clin Pharmacol Biopharm. 1979;17:476–481.

3.     Shim JS, Matsui Y, Bhat S, Nacev BA, Xu J, Bhang HE, Dhara S, Han KC, Chong CR, Pomper MG, et al. Effect of nitroxoline on angiogenesis and growth of human bladder cancer. J Natl Cancer Inst. 2010;102:1855–1873.

4.     Lazovic J, Guo L, Nakashima J, Mirsadraei L, Yong W, Kim HJ, Ellingson B, Wu H, Pope WB. Nitroxoline induces apoptosis and slows glioma growth in vivo. Neuro Oncol. 2015;17:53–62

5.     Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE, Ding WQ. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline) Cancer Lett. 2011;312:11–17.

6.     Mirković B, Renko M, Turk S, Sosič I, Jevnikar Z, Obermajer N, Turk D, Gobec S, Kos J. Novel mechanism of cathepsin B inhibition by antibiotic nitroxoline and related compounds. Chem Med Chem. 2011;6:1351–1356.

7.     Gupta SC, Sung B, Prasad S, Webb LJ, Aggarwal BB. Cancer drug discovery by repurposing: Teaching new tricks to old dogs. Trends Pharmacol Sci. 2013;34:508–517.

 

 

 

Received on 04.02.2019                    Modified on 18.02.2019

Accepted on 05.03.2019                   ©AJRC All right reserved