Aljamali N. M, Jawad S. F. Preparation, Diagnosis and Evaluation of Cyclic-Tryptophan Derivatives as Anti Breast Cancer Agents. Biomed Pharmacol J 2021;14(4).

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Manuscript received on :26-08-2021
Manuscript accepted on :20-11-2021
Published online on: 01-12-2021

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Plagiarism Check: Yes
Reviewed by: Dr. Wael Wahid  
Second Review by: Dr Motavalizadeh  
Final Approval by: Dr. Ayush Dogra

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Nagham Mahmood Aljamali^1* and Sabrean Farhan Jawad²

¹Department of Chemistry ,Synthetic Organic Chemistry ,Iraq.

²Department of Pharmacy, Al-Mustaqbal University College, Babylon, Iraq.

Corresponding Author E-mail: dr.nagham_mj@yahoo.com

DOI : https://dx.doi.org/10.13005/bpj/2296

Abstract

The importance of research lies in the treatment of cancerous tumors due to the spread of cancerous tumors in recent decades, so researchers have to insist on finding alternative and more treatments safe from chemotherapy and radiation, which are derivatives of some amino acids, which we attended in our current research. Also, some research showed that taking tryptophan for 3 days before exercise can improve energy and efficiency during exercise, but other preliminary research shows that taking tryptophan during exercise does not improve endurance during cycling exercises. For a few days before exercise to notice any benefit. In this research, we prepared derivatives of cyclic tryptophan and studied their efficacy as anti-tumors, and they gave good results in reducing the size of cancerous tumors and reducing their spread in the body., then sympathy all synthesized  new cyclic-tryptophan compounds  by numerous techniques (FT.IR ,H.NMR)–spectrophotometric, other  physical and chemical properties ,with studying for one of  new prepared  derivatives as anti breast cancer.

Keywords

Anti Breast; Anticancer; Heterocyclic; Tryptophan; Triazole

Introduction

In 1901, Frederick Hopkins was able to isolate tryptophan for the first time. Hopkins extracted tryptophan from hydrolyzed casein, successfully extracting (4-8 g) of tryptophan from (600 g) of crude casein[1,2]. Tryptophan is a less common amino acid in proteins, but it plays an important structural or functional roles wherever it is found. For example, the residues tryptophan and tyrosine play special roles in ‘fixing’ membrane proteins within the cell membrane. In addition, the functions of tryptophan include being a vital precursor to compounds^3-5., Tryptophan stimulates serotonin levels in the brain, which can treat depression and anxiety. Therefore, you can take tryptophan supplements to reduce these indications ^6-8. Tryptophan helps increase growth hormones, so it is essential for the proper growth of children and infants. Tryptophan is used to treat insomnia, due to the presence of serotonin, which is useful for controlling sleep patterns^9-11. People who suffer from migraines are advised to take doses of tryptophan regularly, and to eat foods rich in tryptophan, which also helps prevent anxiety attacks, which improves a person’s reactions. It works to reduce appetite for food, because serotonin helps to make you feel satiated and reduce food intake. Thus, losing weight helps reduce diabetes and problems related to cardiovascular disease^12-14. The body needs tryptophan to produce niacin, which helps generate good cholesterol and lower bad cholesterol. Foods rich in tryptophan also help convert carbohydrates into energy and maintain a healthy digestive system, skin, hair and eyes^15-17., After we absorb tryptophan from food, our bodies convert it into 5-hydroxytryptophan, an amino acid that works in the brain and central nervous system by increasing the production of the chemical serotonin, and after our bodies convert it to this amino acid^18-22, it then turns into serotonin, melatonin^23-27 and Vitamin B6 (nicotinamide).

Some studies claim that tryptophan supplements may be effective as a sleep treatment and antidepressant. These findings are associated with its role in the synthesis of serotonin and melatonin^28-30. Excessive encouragement of serotonin on postsynaptic (5-HT1A and 5-HT2A) receptors at the central and peripheral levels can have negative consequences for the organism^31-34. This is known as serotonin syndrome and can be fatal. Although this syndrome can be caused by taking medications (eg, Prozac) or using drugs (eg, LSD, MDMA, methylphenidate, bath salts…), it is not likely to be caused by the consumption of nutritional supplements^35-39.

Scheme 1: Trytophan Click here to view scheme

Experimental  Part

Because of the importance of the prepared compounds in this research that they were studied as anti-cancer agents, we were keen to provide materials with high purity and from international companies with  high technology in the production of chemicals. Also, the measurements were made on the following devices represented by  ((FT-IR spectra (FT-IR 8300 Shimadzu) in  the range (400-4000) cm^-1 with KBr-discs., ¹H.NMR–Spectra with (DMSO)–solvent .,besides to anti breast cancer studies.

Synthesis Progressions ^8-12

Preparation Path of  Compound {1}

Compound {1} formatted  by reaction of  tryptophan (0.01 mole) with thiosemicarbazide (0.01 mole)  in presence of (5% of NaOH) with mechanical rotation for (16 hrs) in absolute ethanol permitting to mentioned methods^8-12 to produce precipitation that acts compound{1},the last step ,filtered ,dried ,then recrystallized to give  pure compound.

Preparation Path of  Compound{2}

Compound {2} formatted  by reaction of  compound{1} (0.01 mole) with chloroacetoyl chloride (0.02 mole)  in presence of (K₂CO₃) with mechanical rotation for (4 hrs) permitting to methods^8-12 to yield  precipitation that acts  compound{2},the last step ,filtered ,dried ,then recrystallized to give  pure compound.

Preparation Path of  Compound{3}

Compound {3}cyclized  by cyclization reaction of  compound{2} (0.01 mole) with in presence of (K₂CO₃) with mechanical rotation and  reflux for (6 hrs) permitting to methods^8-12 to yield  precipitation that acts  compound{3},the last step ,filtered ,dried ,then recrystallized to give  pure compound.

Preparation Path of  Compound{4}

Compound {4} formatted  by reaction of  compound {3} (0.01 mole) with benzaldehyde (0.01 mole)  in presence of (5% of NaOH) with mechanical rotation for (12 hrs) in absolute ethanol permitting to mentioned methods^8-12 to produce precipitation that acts  compound{4},the last step ,filtered ,dried ,then recrystallized to give  pure compound.

Preparation Path of  Compound{5}

Compound{5} formatted  by reaction of  compound{3} (0.01 mole) with  m-nitrobenzaldehyde (0.01 mole)  in presence of (5% of NaOH) with mechanical rotation for (13 hrs) in absolute ethanol permitting to mentioned methods^8-12 to produce precipitation that acts  compound{5},the last step ,filtered ,dried ,then recrystallized to give  pure compound.

Scheme 2: Synthesis of Compounds{1 ,2 ,3} Click here to view scheme

Scheme 3: Synthesis of Compounds{4 , 5} Click here to view scheme

Results  and  Discussion

The prepared  tryptophan-derivatives  have been premeditated  by different  chemical  performances  and  studies  against cancerous cells:

Spectral  Evidences of prepared Compounds

FT.IR- Investigation of  Manufactured Derivatives

The bands of important  groups  in  spectra  provided strong evidences  for  new synthesized  compound via  disappearance  of  bands and  appearance  other  new  bands  that  point to  formation of  the new derivatives  that represented by :

Compound {1}: appearance bands  at (3282 , 3300)Cm^-1  due to (NH₂) of amine group, band  at (3223)Cm^-1  due to (NH) of amine group in triazole  cycle, also at  (2445)Cm^-1  due to (SH) of thiol group, band  at  (1652)Cm^-1 due to (C=N) of endocycle  of triazole,  at  (2978)Cm^-1  caused by (CH) aliphatic permitting to literature ¹⁶ .

Compound {2}: appearance band  at (3369)Cm^-1 due to (NH) of amine group in tryptophan, band  at  (1184)Cm^-1 due to (S-CH₂) of sulfide group, also at (1664)Cm^-1 caused by (C=N) of endocycle  of triazole, band  at  (2918)Cm^-1 by reason of (CH) aliphatic, at  (792)Cm^-1  as a result of (C-Cl), band  at  (1681)Cm^-1  due to (C-CO) amide group.

Compound {3}: appearance band at (3421)Cm^-1 caused by (NH) of amine group in tryptophan, band  at  (1180)Cm^-1 due to (S-CH₂) of sulfide group, band at (1643)Cm^-1 down to (C=N) of endocycle  of triazole, band at (2954)Cm^-1 due to (CH) aliphatic, band  at  (1664)Cm^-1 down to (C-CO) amide group.

Compound {4}: appearance band at (3355)Cm^-1 by reason of (NH) of amine group in tryptophan, band at (1148)Cm^-1 due to (S-CH₂) of sulfide group, band at (1655)Cm^-1 due to (C=N) of endocycle  of triazole, band  at  (2919)Cm^-1 due to (CH) aliphatic, band at (1679)Cm^-1 due to (C-CO) amide group, band  at (3092)Cm^-1 due to (CH=C) alkene , according to literature ¹⁶.

Compound {5}: appearance band  at (3310)Cm^-1 by reason of (NH) of amine group in tryptophan, band at (1133)Cm^-1 down to (S-CH₂) of sulfide group, at (1647)Cm^-1 due to (C=N) of endocycle  of triazole, band at (2906)Cm^-1 down to (CH) aliphatic, band  at  (1682)Cm^-1 down to (C-CO) amide group, band  at (3097)Cm^-1 down to (CH=C) alkene, bands at (1327 , 1511)Cm^-1  due to (NO₂) nitro group., Other frequencies  appeared in some figures (1 , 2) .

Figure 1: I.R  Spectrum of The formatted Compound {2} Click here to view figure

Figure 2: I.R -Spectrum of The formatted Compound {3} Click here to view figure

¹H.NMR- Investigation of  Manufactured Derivatives

The signals of important  groups  in  spectra  provided strong evidences  for  new synthesized  compound via  disappearance  of  peaks and  appearance  other  new  peaks  that  point to  formation of  the new derivatives  that represented by : signals at (4.55 to  5.00) due to proton of amine group (NH) ,signals at (10. 12  to   10. 80) due to proton  of  amide (-NH-CO), signals  at (6. 60-7. 95) due to protons of  phenyl  ring in  compounds {2 ,3 , 4, 5}respectively, signal at (3.05) due to proton of (CO-CH₂-S) in compounds {2 ,3}respectively , signal at (4.45) due to proton of (CH=C) of  alkene in compounds {4 ,5}respectively permitting to literature ⁽¹⁶⁾ .,Some peaks  in some  figures (3, 4).   

Figure 3: H.NMR-Spectrum of Compound{2} Click here to view figure

Figure 4: H.NMR-Spectrum of Compound{4} Click here to view figure

Some physical and Chemical characterization:

All other physical and chemical analysis besides to some description in Table (1): 

Table 1: Some  Physical Properties  of New Compounds

Analysis of derivatives with  Breast Cancer 

The study was conducted to test the effectiveness of medicinal derivatives through the methods listed in the references^{17, 18} .

Table 2: Mean Percentage (%) for each cell line (Respond to Treatment) for  Derivative{2}.

Figure 5: Effect  of  Tryptophan-Derivative [2] on Breast Cancer Cells Click here to view figure

Conclusion

The manufactured of Tryptophan-Derivative [2]  gave multiple strong evidences about structures of compounds were stable, and all Tryptophan-Derivatives have high solubility in ethanol , DMSO, Methanol  and other solvents. And have good activity against  breast breast cancer cells.

Acknowledgment

we would like to express our heartfelt thanks to health-Lab for providing assistance samples of breast cancer for studying

Ethical clearance

Ethics committee refer that there is no plagiarism and there is no mistakes or wrong results  in this work.

Conflict of interest

The authors declare that there is no conflict of interest.

Funding source

There are no funding sources.

References

1. Nagham Mahmood Aljamali., 2015. Synthesis and Chemical Identification of Macro Compounds of (Thiazol and Imidazol)”.,Research J. Pharm. and Tech, 8,1, 78-84., DOI: 10.5958/0974-360X.2015.00016.5.
   CrossRef
2. Miaid Mohmed ,Nagham Mahmood Aljamali ,Sabreen Ali Abdalrahman., Wassan Ala Shubber., “Formation of Oxadiazole Derivatives Ligands from Condensation and Imination Reaction with References To Spectral Investigation, Thermal and Microbial Assay”., Biochem. Cell. Arch., 2018 ,18, 1, pp. 847-853.
3. Pradhan, L.-P. Xu, S. Chen. Janus nanoparticles by interfacial engineering. Adv. Funct. Mater., 17 (14) (2007), pp. 2385-2392.
   CrossRef
4. Nagham Mahmood Aljamali. 2016. “Synthesis and Biological Study of Hetero (Atoms and Cycles) Compounds”, Der Pharma Chemica, 8,6, 40-48.
5. Thomas L. Gilchrist “Heterocyclic Chemistry” 3rd ed. Addison Wesley: Essex, England, 1997. 414 pp. ISBN 0-582-27843-0.
6. Edon Vitaku, David T. Smith, Jon T. Njardarson (2014). “Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals”. J. Med. Chem. 57: 10257-10274. doi:1021/jm501100b
   CrossRef
7. Wang, Cuiling; Yan, Jiaxu; Du, Mo; Burlison, Joseph A.; Li, Chi; Sun, Yanni; Zhao, Danqing; Liu, Jianli (2017). “One step synthesis of indirubins by reductive coupling of isatins with KBH4”. Tetrahedron . 73 (19): 2780–2785. doi:1016/j.tet.2017.03.077.
   CrossRef
8. Nagham Mahmood Aljamali., “The Various Preparation Methods in Synthetic Chemistry”.,1 Edt. ,Evincepub Publishing house, 2019., ISBN :978-93-88277-82-2.
9. Nagham Mahmood Aljamali, “Effect of Conditions and Catalysis on Products” .,1th –Edition, 2021 , Eliva Press SRL., ISBN: 9781636482286
10. Nagham Mahmood Aljamali. “Reactions and Mechanisms”.,1 Edt., IJMRA Publication ,2018 .,ISBN : 978- 93-87176-25-6 .
11. Nagham Mahmood Aljamali. “Experimental Methods for Preparation of Mannich Bases, Formazan, Normal and Cyclic Sulfur Compounds”, 1^st edition Evince pub Publishing House;2018, ISBN: 978-93-87905-19-1.
12. Nagham Mahmood Aljamali., “Alternative Methods in Organic Synthesis”.,1th–Edition, Eliva Press SRL, 2020 ., ISBN: 9798680201176.
13. Matheus ME, de Almeida Violante F, Garden SJ. Isatins inhibit cyclooxygenase-2 and inducible nitric oxide synthase in a mouse macrophage cell line. Eur J Pharmacol. 2007; 556 :200–6.
    CrossRef
14. Perro, S. Reculusa, E. Bourgeat-Lami, E. Duguet, S. Ravaine. Synthesis of hybrid colloidal particles: from snowman-like to raspberry-like morphologies Colloids Surf, Physicochem. Eng. Asp., 284 (2006), pp. 78-83.
    CrossRef
15. Pera-Titus, L. Leclercq, J.-M. Clacens, F. De Campo, V. Nardello-RatajPickering interfacial catalysis for biphasic systems: from emulsion design to green reactions., Angew Chem. Int. Ed., 54 (7) (2015), pp. 2006-2021.
    CrossRef
16. Nagham Mahmood Aljamali, “Spectral and Laboratory Diagnostics of  Compounds”., 1th –Edition, 2021, Eliva Press SRL., ISBN: 9781636482118.
17. Nagham Mahmood Aljamali, Imad Kareem Alwan Alsabri., Development of Trimethoprim Drug and Innovation of Sulfazane-Trimethoprim Derivatives as Anticancer Agents ., Biomedical & Pharmacology Journal, March 2020., Vol. 13, (2), p. 613-625 ., http://dx.doi.org/10.13005/bpj/1925 .
    CrossRef
18. Imad Kareem Alwan Alsabri, Hasaneen Kudhair Abdullabass ,Nagham Mahmood Aljamali .,Invention of (Gluta.Sulfazane-Cefixime) Compounds as Inhibitors of Cancerous Tumors., Journal of Cardiovascular Disease Research, 2020,11, 2., 44-55 ., DOI: 10.31838/jcdr.2020.11.02.09 .
    CrossRef
19. Hasaneen Kudhair Abdullabass, Aseel Mahmood Jawad ,Nagham Mahmood Aljamali . Synthesis of drugs derivatives as inhibitors of cancerous cells., Biochem. Cell. Arch, 20 (2) – October 2020.
20. Casagrande, P. Fabre, E. Raphael, M. VeyssieJanus beads: realization and behavior at water oil interfaces., Europhys. Lett., 9 (3) (1989), pp. 251-255.
    CrossRef
21. -J. Zhou, L. Fang, Z. Fan, B. Albela, L. Bonneviot, F. De Campo. .Tunable catalysts for solvent-free biphasic systems: pickering interfacial catalysts over amphiphilic silica nanoparticles., J. Am. Chem. Soc., 136 (13) (2014), pp. 4869-4872.
    CrossRef
22. Mehta SL, Manhas N, Raghubiz R. Molecular targets in cerebral ischemia for developing novel therapeutics . Brain Res Rev. 2007;54:34–66.
    CrossRef
23. Meaaed M, Nagham Mahmood Aljamali, Nadheema A A., “Preparation, Spectral Investigation, Thermal Analysis, Biochemical Studying of New (Oxadiazole -Five Membered Ring)-Ligands”., Journal of Global Pharmacy Technology, 2018;10,1,20-29.
24. Liu, J. Hu, X. Yu, X. Xu, Y. Gao, H. Li. Preparation of Janus-type catalysts and their catalytic performance at emulsion interface., J. Colloid Interface Sci., 490 (2017), pp. 357-3564.
    CrossRef
25. Nagham Mahmood Aljamali. Survey on Methods of Preparation and Cyclization of Heterocycles. International Journal of Chemical and Molecular Engineering. 2020; 6(2): 19–36p.
26. W. Seh, S. Liu, S.-Y. Zhang, M.S. Bharathi, H. Ramanarayan, M. Low. Anisotropic growth of titania onto various gold nanostructures: synthesis, theoretical understanding, and optimization for catalysis., Angew Chem. Int. Ed., 50 (43) (2011), pp. 10140-10143.
    CrossRef
27. Mieaad M, Nagham Mahmood Aljamali, Wassan Ala Shubber., Sabreen Ali Abdalrahman .”New Azomethine- Azo Heterocyclic Ligands Via Cyclization of Ester”., Research Journal of Pharmacy and Technology, 2018, 11,6, 2555-2560 ., DOI : 5958/0974-360X. 2018. 00472.9 .
    CrossRef
28. A. Ismail, D.W. Bahnemann, I. Bannat, M. Wark Gold nanoparticles on mesoporous interparticle networks of titanium dioxide nanocrystals for enhanced photonic efficiencies ,J. Phys. Chem. C., 113 (17) (2009), pp. 7429-7435.
    CrossRef
29. Shafiq, Iqrash; Shafique, Sumeer; Akhter, Parveen; Yang, Wenshu; Hussain, Murid . (2020) . “Recent developments in alumina supported hydrodesulfurization catalysts for the production of sulfur-free refinery products: A technical review”. Catalysis Reviews. 0: 1–86.
    CrossRef
30. Nagham Mahmood Aljamali, Intisar Obaid Alfatlawi. “Synthesis of Sulfur Heterocyclic Compounds and Study of Expected Biological Activity”, Research J. Pharm. and Tech., 2015, 8,9 ,1225-1242 , DOI: 10.5958/0974-360X.2015 .00224.3.
    CrossRef
31. Wei, Hui; Wang, Erkang (2013). “Nanomaterials with enzyme-like characteristics (nanozymes): next-generation artificial enzymes”. Chemical Society Reviews. 42 (14): 6060–93. doi:1039/C3CS35486E. ISSN 1460-4744. PMID 23740388.
    CrossRef
32. Intisar Obaid Alfatlawi, Nuha S S, Zainab M J ,Nagham Mahmood Aljamali, Intisar O A. “Synthesis of New Organic Compounds Via Three Components Reaction with Studying of (Identification, Thermal Behavior, Bioactivity on Bacteria of Teeth)”., Journal of Global Pharma Technology. 2017;11,9, 157-164.
33. Naumann d’Alnoncourt, Raoul; Csepei, Lénárd-István; Hävecker, Michael; Girgsdies, Frank; Schuster, Manfred E.; Schlögl, Robert; Trunschke, Annette (2014). “The reaction network in propane oxidation over phase-pure MoVTeNb M1 oxide catalysts”. Journal of Catalysis. 311: 369–385.
    CrossRef
34. Mokrani, Touhami; van Reenen, Albert; Amer, Ismael (2015).”Molecular weight and tacticity effect on morphological and mechanical properties of Ziegler–Natta catalyzed isotactic polypropylenes”. Polímeros. 25 (6): 556–563. doi:1590/0104-1428.2158 . ISSN 0104-1428.
    CrossRef
35. Shireen R. Rasool, Nagham Mahmood Aljamali ,Ali Jassim Al-Zuhairi., Guanine substituted heterocyclic derivatives as bioactive compounds., Biochem. Cell. Arch. Vol. 20, Supplement 2, pp. 3651-3655, 2020 ., DocID: https://connectjournals.com/03896.2020.20.3651.
    CrossRef
36. Dub, Pavel A.; Gordon, John C. (2018). “The role of the metal-bound N–H functionality in Noyori-type molecular catalysts”. Nature Reviews Chemistry. 2 (12): 396–408.
    CrossRef
37. Aseel Mahmood Jawad., Nagham Mahmood Aljamali, Saher Mahmood Jawd., Development and Preparation of ciprofloxacin Drug Derivatives for Treatment of Microbial Contamination in Hospitals and Environment, Indian Journal of Forensic Medicine & Toxicology, 2020 ,14, 2, p:1115-1122.
38. S FJawad, Nagham Mahmood Aljamali , Preparation, Investigation and Study of Biological Applications of Tyrosine Derivatives against Breast Cancer Cells ., NeuroQuantology ,September 2021 ,Volume 19 , Issue 9 , Page 117-125 .,doi: 10.14704/nq.2021.19.9.NQ21144 .
    CrossRef
39. Clark, Jim (2013). “Types of catalysis”. Chemguide. Bård Lindström and Lars J. Petterson (2003) “A brief history of catalysis” Cattech, 7 (4) : 130–38.
    CrossRef
40. Pisarewicz K, Mora D, Pflueger F, Fields G, Marí F (2005). “Polypeptide chains containing D-gamma-hydroxyvaline”. J Am Chem Soc. 127 (17): 6207–15
    CrossRef