Nitro-Imidazole Derivatives an Unique Class for Diverse Biological Activity: A Review

C.P. Meher*, S.P. Sethy, A.M. Rao

Department of Pharmaceutical Chemistry, Maheswara Institute of Pharmacy, Patancheru, Hyderabad.

*Corresponding Author E-mail: chaitanyameher84@gmail.com

ABSTRACT:

Imidazole is one of the important heterocyclic compound in the aromatic world of medicinal chemistry. It is also a important constituent of several natural products including purine, histidine and nuclic acid. But substitution of nitro group in the imidazole or the nitroimidazole enhances the solubility and bioavailability parameter of proposed poorly soluble lead molecule. The application of these nitroimidazole containing drugs has widened in various simple and complex diseases. Nitroimidazole derivative are widely used as the anaerobic anti bacterial, antiprotozoal, antifungal, anti HIV agents, radiosensitizers, hypoxic marker etc. Substitution of the nitro group on the different position (2,4,5) of imidazole show same physical properties but their derivative show variable pharmacological activity. The present review is concerned with the comparative work reported, their chemistry and biological activities of 2-nitroimidazole, 4- nitroimidazole and 5- nitroimidazole derivatives during the past years.

KEY WORDS: Nitro imidazole, antibacterial, antifungal, antihistamine, antiparasitic, antiamoebic, antoprotozoal, hypoxic marker.

INTRODUCTION:

In the past few decades there has been a hiatus in the momentum of research and discovery of novel medicinal compound. Heterocyclic compounds are found to be more promising and interesting field due to its diverse pharmacological effect. Now a days the scientist were giving more emphasis on nitroimidazole compounds for its variable effect according to their different substitution and surprisingly it is active against diverse field of therapeutics disease. The point to be consider is that while studying the nitro imidazole derivative, the physical properties of all the three(2,4,5 position) nitro substituted imidazole nucleus has the the same  properties which are listed in the table-1 .

Table-1

2-nitro-1H-imidazole	4-nitro-1H-imidazole	5-nitro-1H-imidazole
PROPERTIES: · Molecular Formula=C3H3N3O2 · Formula Weight = 113.07482 · Composition =  C(31.87%) H(2.67%) N(37.16%) O(28.30%) · Molar Refractivity = 25.32 ± 0.3 cm^3 · Molar Volume =72.8 ± 3.0 cm^3 · Parachor = 216.5 ± 4.0 cm^3 · Index of Refraction =1.612 ± 0.02 · Surface Tension= 78.1 ± 3.0 dyne/cm · Density= 1.552 ± 0.06g/cm^3 · Polarizability = 10.03 ± 0.5 10^-24cm^3 · Monoisotopic Mass = 113.022526 Da · Nominal Mass = 113 Da · Average Mass = 113.0748 Da	PROPERTIES: · Molecular Formula= C3H3N3O2 · Formula Weight = 113.07482 · Composition =  C(31.87%) H(2.67%)N(37.16%)O(28.30%) · Molar Refractivity = 25.32 ± 0.3cm^3 · Molar Volume = 72.8 ± 3.0 cm^3 · Parachor = 216.5 ± 4.0 cm^3 · Index of Refraction = 1.612 ± 0.02 · Surface Tension =78.1 ± 3.0 dyne/cm · Density =1.552 ± 0.06 g/cm^3 · Polarizability = 10.03 ± 0.5 10^-24cm^3 · Monoisotopic Mass = 113.022526 Da · Nominal Mass = 113 Da · Average Mass = 113.0748 Da	PROPERTIES: · Molecular Formula = C3H3N3O2 · Formula Weight = 113.07482 · Composition =  C(31.87%) H(2.67%) N(37.16%) O(28.30%) · Molar Refractivity = 25.32 ± 0.3 cm^3 · Molar Volume = 72.8 ± 3.0 cm^3 · Parachor = 216.5 ± 4.0 cm^3 · Index of Refraction = 1.612 ± 0.02 · Surface Tension = 78.1 ± 3.0 dyne/cm · Density = 1.552 ± 0.06 g/cm^3 · Polarizability = 10.03 ± 0.5 10^-24cm^3 · Monoisotopic Mass = 113.022526 Da · Nominal Mass          = 113 Da · Average Mass = 113.0748 Da

In spite of the same physical properties of the above mention nitroimidazole,they can be used for diverse biological activity according to their content substitutions.

The nitroimidazoles have a wide range of biological properties that provide an increasing number of therapeutic applications. Some properties are common to all nitroimidazoles whereas others are characteristic only of certain compounds. Considerable insight may be gained into the mechanism of action of the nitroimidazoles by seeking correlations between their chemical and biological properties. Thus the reduction potential of the nitro group of a nitroimidazole tends to correlate with its relative potency as a mutagen, cytotoxin, or radiation sensitizer. The apparent obligatory rule of nitro group reduction for biological activity explains why 5-nitroimidazoles such as tinidazole and metronidazole exhibit selective toxicity for anaerobic micro-organisms. Such organisms would be expected to carry out more readily the reduction that is necessary to activate the nitroimidazole. Furthermore, anoxic conditions favour nitroimidazole activity because oxygen interferes with nitro group reduction and thus the formation of the postulated reactive form of the nitroimidazole. By changing the chemical substituents at the 1-and 2-positions of a 5-nitroimidazole one may alter both its microbiocidal activity spectrum and its human pharmacokinetic properties. The result may be a drug that improves the treatment of trichomoniasis, amoebiasis, or giardiasis, or the treatment or prophylaxis of anaerobic bacterial infections. Alternatively, structural modifications of the 5-nitroimidazoles may yield drugs with activity against a broader range of protozoal and bacterial infections.

5-nitroimidazoles area well-established group of antiprotozoal and antibacterial agents that inhibit the growth of both anaerobic bacteria and certain anaerobic protozoa, such asTrichomonas vaginalis, Entamoeba histolytica and Giardia lamblia. The important antibacterial and antiprotozoal activities of nitroimidazoles are associated with reductive metabolism methods. 2-Nitroimidazoles play a major role as bioreductive markers for tumour hypoxia, as radiosensitizers.4-nitroimidazole are effective against amoebic, H.I.V, transplantation of organs, antiparasitic etc.

Given below is a brief account of various alterations conducted on nitro imidazole ring containing few important marketed drugs, drugs under clinical trial and their associated biological activities.

5-NITRO IMIDAZOLES

1.Azanidazole 4-[(E)-2-(1-methyl-5-nitro-1H-imidazol- 2-yl)ethenyl]pyrimidin-2-amine	It is used in gynecology for the treatment of trichomonal infections.	Marchionni M.et.al^1
2 . Dimetridazole 1,2-Dimethyl-5-nitroimidazole	Dimetridazole is a drug that combats protozoan infections.	D. S. Fernied.et.al^2
3. Metronidazole 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol	Metronidazole is an antibiotic, amebicide, and antiprotozoal.	Ebel, K. et.al^3 Pandeya S.N.et al^4 Bently and driver’s.et.al^5
4. Nimorazole 4-[2-(5-nitro-1H-imidazol-1-yl)ethyl]morpholine	Nimorazole  is used as an hypoxic radio sensitizer in larynx and pharynx carcinoma.	Jens Overgaarda.et.al^6
5. Ornidazole 1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol	Ornidazole is a drug that cures some protozoan infections,anti amoebic.	Pandeya S.N.et al^4 Rutgeerts P.et.al^7
6. Secnidazole 1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol	Secnidazole  is a nitroimidazole anti-infective.	Clinical Microbiology and Infection^8
7. Tinidazole 1-(2-ethylsulfonylethyl)-2-methyl-5-nitro-imidazole	It is an anti-parasitic drug used against protozoan infections.	Pandeya S.N.et al^4 David N. Gilbert.et.al ^9
8. Carnidazole O-Methyl [2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]carbamothioate	Carnidazole is an antiprotozoal drug .	Merck .et.al.^10
9. Fexinidazole 2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole	Fexinidazole is an antiparasitic agent.	W.Seidenath.et.al.^11
10. Ipronidazole 2-Isopropyl-1-methyl-5-nitro-1H-imidazole	Ipronidazole is an antiprotozoal drug	Assandri, A.et.al ^12
11. Ronidazole (1-Methyl-5-nitro-1H-imidazol-2-yl)methyl carbamate	Ronidazole is an antiprotozoal agent	Sullivan, T.et.al ^13
12. Metronidazole [2-(2-methyl-5-nitro-imidazol-1-yl)-ethanol	Antifungal and antiprotozoal activities	Alka Mithal.et.al ^14
13. 5-Nitromegazol 5-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-amine	Trypanocidal nitroimidazoles	Alka Mithal.et.al ^14
14. 2-[(E)-2-(4-chlorophenyl)ethenyl]-1-methyl-5-nitro-1H-imidazole	Effective against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis	Jacqueline A. UpcroftHYPERLINK "file:///C:\Users\Sarada\Desktop\344.full.htm" \l "aff-1" 1.et.al^15
15. 4-{1-methyl-2-[(E)-2-(5-nitro-1H-imidazol-2-yl)ethenyl]-1H-imidazol-5-yl}benzene-1,2-diol	Effective against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis	Jacqueline A. UpcroftHYPERLINK "file:///C:\Users\Sarada\Desktop\344.full.htm" \l "aff-1" 1.et.al^15
16. 2-[(Z)-1,2-dichloro-2-(1-methyl-5-nitro-1H-imidazol-2-yl)ethenyl]-1-methyl-1H-imidazol-5-amine	Effective against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis.	Jacqueline A. UpcroftHYPERLINK "file:///C:\Users\Sarada\Desktop\344.full.htm" \l "aff-1" 1.et.al^15
17. (2E)-4-methyl-2-[(1-methyl-5-nitro-1H-imidazol-2-yl)methylidene]-4-nitropentanal	Effective against Metronidazole-Susceptible and -Resistant Giardia, Trichomonas, and Entamoeba spp	Jacqueline A. UpcroftHYPERLINK "file:///C:\Users\Sarada\Desktop\344.full.htm" \l "aff-1" 1.et.al^15
18. 2-[3-chloro-2-(chloromethyl)prop-1-en-1-yl]-1-methyl-5-nitro-1H-imidazole	Effective against Metronidazole-Susceptible and -Resistant Giardia, Trichomonas, and Entamoeba spp	Jacqueline A. UpcroftHYPERLINK "file:///C:\Users\Sarada\Desktop\344.full.htm" \l "aff-1" 1.et.al^15

4-NITROIMIDAZOLE :

19.4-nitro megazole 5-(1-methyl-4-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-amine	Trypanocidal nitroimidazoles	Alka Mithal.et.al ^14
20. 1-[4-(1-benzyl-2-ethyl-4-nitro-1H-imidazol-5-yl)piperazin-1-yl]-2-chloroethanone	Anti HIV Agent	Alka Mithal.et.al ^14
22. phenyl 1-methyl-4-nitro-1H-imidazole-5-sulfonate	Used as a sensitizer of hypoxic mammalian cells	Adams, G. E.et.al ^16
23. 2-chloro 4-nitroimidazole	Anti amoebic	Watras, J.et.al ^17
24.Azathioprine 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7H-purine	Azathioprine is an immunosuppressive drug used in organ transplantation and autoimmune diseases and belongs to the chemical class of purine analogues	Maltzman, J. S.et.al^18 Patel, A. A.et.al.^19
25. 1-methyl-4-nitro-5-phenyl-1H-imidazole	Significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al ^20
26. 5-(3-fluorophenyl)-1-methyl-4-nitro-1H-imidazole	Significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al ^20
27. 5-(4-methoxyphenyl)-1-methyl-4-nitro-1H-imidazole	Significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al^20
28. 5-(4-chlorophenyl)-1-methyl-4-nitro-1H-imidazole	Significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al^20
29. 5-chloro-1-methyl-4-nitroimidazole	Significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al^20
30 1-methyl-5-(4-methylphenyl)-4-nitro-1H-imidazole	Significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al^20
31. 2-methyl-4-nitro-1-trityl-1H-imidazole	Antifungal	Soghra Khabnadideha.et.al^21
32- 1[4-Methoxyphenyl-diphenylmethyl]-2-methyl-4-nitroimidazole	Antifungal	Soghra Khabnadideha.et.al^21
33. 1[Bis-4-methoxyphenyl-phenylmethyl]-2-methyl-4-nitroimidazole	Antifungal	Soghra Khabnadideha.et.al^21
34. 5-(4-fluorophenyl)-1-methyl-4-nitro-1H-imidazole	These compounds indicated significant antiparasitic activities against Entamoeba histolytica and Giardia intestinalis	Haythem A.et.al ^20

2-NITROIMIDAZOLE :-

35. Benznidazole N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide	Benznidazole is an antiparasitic agent.	Alka Mithal.et.al ^14
36.Misonidazole (RS)-1-Methoxy-3-(2-nitroimidazol-1-yl)propan-2-ol	Misonidazole is a radiosensitizer used in radiation therapy to cause normally resistant hypoxic tumor cells to become sensitive to the treatment	Hasan Tashtoush .et.al^22
37.TH-302 N,N′-Bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester	Used in experimental cancer treatment	J. Thomas Pento.et.al ^23 Duan J.et.al^24
38.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
39.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
40.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
41.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
42.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
43.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
44.	Used as cancer imaging and radiotherapeutic agents	Zha Z.et.al ^25
45.EF5 2-(2-Nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide	EF5 is a nitroimidazole used in oncology research.^[1] Due to its similarity in chemical structure to etanidazole, EF5 binds in cells displaying hypoxia.	Evans.et.al^26
46. N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide	Trypanocidal nitroimidazoles	Alka Mithal.et.al ^14
47. SR-4554	It is used as Noninvasive Hypoxia Marker .	Beatrice M. Seddon.et.al^27
48. GPU-167	It is Used as hypoxic marker	Kensuke Okuda.et.al ^28
49.	^123I-Labeled iodoazomycin arabinoside (IAZA) is a marker of hypoxia in vivo.	Daria Stypinski.et.al ^29
50.Etanidazole N-(2-hydroxyethyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide	Etanidazole is a nitroimidazole drug used for its radiosensitizing properties.	Evans, et.al ^26
51. Fluromisonidazole (2R)-1-fluoro-3-(2-nitro-1H-imidazol-1-yl)propan-2-ol	Radiopharmaceuticals for imaging hypoxia	Koh W-J.et.al^30

Use of 2-Nitroimidazole over Other substituted nitroimidazole :-

All anaerobes have redox potentials of about -430 to 460 mV, which is typical for ferredoxin, whereas the most negative redox potential in aerobes are those of the NAD/NADH and NADP/NADPH couples at about -320 mV. The 5-nitroimidazole, metronidazole (METRO), has a reduction potential of anaerobes -415 mV and is efficiently reduced in anaerobes but not in aerobes. Thus the 5-nitroimidazole activity against gram-positive and gram-negative bacteria and protozoa. In order to achieve useful reduction in aerobes the reduction potential of nitroimidazole group must be reduced. This is done by charging the substitution pattern from the 5- nitroimidazole of METRO to the 2-nitroimidazole of misonidazole (MISO), which has a reduction potential of -389 mV. Among the different nitroimidazoles viz. 2- ,4-, and 5- nitroimidazole, the 2-nitroimidazole possess the more positive single-electron reduction potential (SERP) value, between -250 to -350 mV, with respect to standard hydrogen electrode (SHE).[31]The SERP value of 4-nitroimidazole ranges from -500 mV to -550 mV, whereas, for the 5- nitroimidazole SERP range from -400 to -450 mV with respect to SHE. The exact value of the SERP depends on the substitution in the nitroimidazole ring.

CONCLUSION:

Vast number of imidazole containing compounds have been synthesized and evaluated for their biological activity. Nitroimidazoles are a class of compounds that are selectively trapped hypoxic cells. introduction of a nitro group on heterocyclic such as imidazole give them bacterio-static properties. 5-nitroimidazole (azomycin) was active against infection associated with anaerobic conditions. Over the intervening 50 years many nitroimidazole analogs have been synthesized, leading to antibiotics such as metronidazole, tinidazole, nimorazole and ornidazole which are effective against bacteria and protozoa. 5-Nitroimidazoles are more active against anaerobes than 4-nitro isomers. Antianaerobic and antiamoebic activities generally run parallel in these classes of compounds.2-nitroimidazole are basically used as hypoxic marker.

REFERENCE:

1. Marchionni M, Innocenti Degli A, Penna C (1981). "Combined systemic and topical treatment of trichomoniasis vaginalis with azanidazol".  18–20

2. D. S. Fernied,. A. Ware* and R. W. A. Park “The effect of the Nitroimidazile Drug metridazole Microaerophilliccampy lobacters” J. Med. Microbil.-Vol. 10 (1977).

3. Ebel, K.; Koehler, H.; Gamer, A. O.; Jackh, R. (2005), "Imidazole and Derivatives”

4. S.N.Pandeya, Medicinal Chemistry, vol-2, S.G.publisher, 3rdedition, 2003 [739,740,741,677,722,724,733,635,637,956, 652, 661,681]

5. Bently and driver’s text book of pharma chemistry, 646-647

6. Jens Overgaarda,, Hanne Sand Hansenb, Marie Overgaardc, Lars Bastholtd,Anne Berthelsene, Lena Spechte, Birgit Lindeløvb, Karsten Jørgensenf “A randomized double-blind phase III study of nimorazole as a hypoxicradiosensitizer of primary radiotherapy in supraglottic larynxand pharynx carcinoma”. Results of the Danish Headand Neck Cancer Study (DAHANCA) Protocol 5-85 ”Radiotherapy and Oncology 46 (1998) 135–146.

7. Rutgeerts P, Van Assche G, Vermeire S, (April 2005). Ornidazole for prophylaxis of ostoperative Crohn's disease recurrence: a randomized, double-blind, placebo-controlled trial"

8. Clinical Microbiology and Infection 9 (2): 110–113

9. David N. Gilbert, M.D., The Sanford Guide to Antimicrobial Therapy 2010. p. 18.

10. Merck Index, 11th Edition, 1855

11. W; Seidenath, H (1983). "The activity of fexinidazole (HOE 239) against experimental infections with Trypanosoma cruzi, trichomonads and Entamoeba histolytica". Annals of tropical medicine and parasitology: 13–26.

12. Assandri, A., Perazzi, A., Zerilli, C.F., Ferrari, O., and Martenlli, E. (1978). Metabolism of 5-isopropyl-1-methyl-2-nitro-1H-imadozole. Drug Metab. Dispos., 6, 109-113.

13. Sullivan, T. W.; Grace, O. D.; Aksoy, Ayhan. (1977). "Influence of level, timing and duration of ronidazole water medication on histomoniasis in turkeys". Poultry Science 56 (2): 571–576

14. Alka Mithal “Synthetic Nitroimidazoles:Biological Activities andMutagenicity Relationships” Scientia pharmaceutica, 2009; 77: 497–520

15. Jacqueline A. Upcroft, Linda A. Dunn, Janelle M. Wright, Kamel Benakli, Peter Upcroft and Patrice Vanelle” 5-Nitroimidazole Drugs Effective against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis” Antimicrob. Agents Chemother. January 2006 vol. 50 no. 1 344-347

16. Adams, G. E., Ahmed, I., Fielden, E. M., O'neill,P. and Stratford, I. J. (1980a) The development of some nitroimidazoles as hypoxic cell radiosensitizers. Cancer Clin. Trials, 3, 37.

17. Watras, J., Widel M., Suwinski J., Salwinska E. 2-Chloro-4-nitroimidazole radiosensitizers of hypoxic tumor cells in vivo. Journal Neoplasma: 253.

18. Maltzman, J. S.; Koretzky, G. A. (2003). "Azathioprine: Old drug, new actions". Journal of Clinical Investigation 111 (8): 1122–1124.

19. Patel, A. A.; Swerlick, R. A.; McCall, C. O. (2006). "Azathioprine in dermatology: The past, the present, and the future". Journal of the American Academy of Dermatology 55 (3): 369–389.

20. Haythem A. Saadeh, Ibrahim M. Mosleh and Mustafa M. El-Abadelah “New Synthesis and Antiparasitic Activity of Model 5-Aryl-1-methyl-4-nitroimidazoles” Molecules, 1420-3049, www.mdpi.com/journal/ molecules.

21. Soghra Khabnadideha, Zahra Rezaeia, Ali Khalafi-Nezhadb, Keyvan Pakshirc, Mohammad Javad Heirana, Hesamedin Shobeiria. Design and Synthesis of 2-Methyl and 2-Methyl-4-NitroImidazole Derivatives as Antifungal Agents. Iranian Journal of Pharmaceutical Sciences 2009: 5(1): 31-36.

22. Hasan Tashtoush, Yaseen Al-Soud, Ahmed Maslat, Mohanad Shkoor and Mahmoud Al-Talib. “Synthesis and Biological Activity of Some New 5-Sulphanyl- 4-nitroimidazole Derivatives” Jordan Journal of Chemistry Vol. 2 No.1, 2007, pp. 11-20

23. J. Thomas Pento (2011). "TH-302". Drugs of the Future” 36 (9): 663–667.

24. Duan J; Jiao, H; Kaizerman, J; Stanton, T; Evans, JW; Lan, L; Lorente, G; Banica, M et al. (2008). "Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs". J. Med. Chem. 51 (8): 2412–20

25. Zha Z, Zhu L, Liu Y, Du F, Gan H, Qiao J, Kung HF. Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radio ligands for tumor imaging. Nucl Med Biol-2011 May; 38(4):501-8. Epub 2011 Feb 4.

26. Evans, Sydney M.; Fraker, Douglas; Hahn, Stephen M.; Gleason, Kristen; Jenkins, W. Timothy; Jenkins, Kevin; Hwang, Wei-Ting; Zhang, Paul; Mick, Rosemarie; Koch, Cameron J (2006). "EF5 binding and clinical outcome in human soft tissue sarcomas". International Journal of Radiation Oncology, Biology, Physics 64 (3): 922–927.

27. Beatrice M. Seddon, Ross J. Maxwell, Davina J. Honess, Rachel Grimshaw, Florence Raynaud, Gillian M. Tozer, and PaulWorkman.“Spectroscopy Validation of the Fluorinated 2-Nitroimidazole SR-4554 as a Noninvasive Hypoxia Marker Detected by Magnetic Resonance” Clinical cancer research

28. Kensuke Okuda, Yasuyuki Okabe, Tetsuya Kadonosono, Takahiro Ueno, Bahaa G M Youssif, Shinae Kizaka-Kondoh, Hideko Nagasawa “Nitroimidazole-tricarbocyanine conjugate as a near-infrared fluorescent probe for in vivo imaging of tumor hypoxia”Journal Article: Bioconjugate Chemistry. 02/2012; 23(3): 324-9.

29. Daria Stypinski, Steve A. McQuarrie, Leonard I. Wiebe, Yun K. Tam, John R. Mercer and Alexander J.B. McEwan “Dosimetry Estimations for ¹²³I-IAZA in Healthy Volunteers” Journal of nuclear medicine

30. Koh W-J, Bergman KS, Rasey JS, Evaluation of oxygenation status during functionated radiotherapy in human nor small cell lung cancer using 18F-MISO-PET, Int J Radiat Oncol Biol Phys,1995,32:391-398

31. P. Wardman, J. Phys. Chem., 1989, 18(4), 1664

Received on 03.10.2012        Modified on 10.10.2012

Accepted on 18.10.2012        © AJRC All right reserved

Asian J. Research Chem. 5(10): October, 2012; Page 1309-1319