I
n the present study, a series of thiazolo[3,2-c]pyrimidines (4,5) have been produced via simple and efficient
synthetic method and their in vitro cytotoxicities have been performed on human breast (MCF-7) and
hepatocellular (HEPG2/C3A) adenocarcinoma cell lines. The results of these in vitro tests revealed that at
least five of thiazolo[3,2-c]pyrimidines exhibited strong cytotoxic effects at very low concentrations, which
were very similar or lower than that of reference anticancer agent, 5-FU, against MCF-7 and HEPG2/C3A cancer
cell lines.
D. Peer, J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit,
R. Langer, Nanocarriers as an emerging platform for
cancer therapy, Nat. Nanotechnol., 2 (2007) 751-760.
F. Arcamone, Doxorubicin: anticancer antibiotics,
(2012) Elsevier, New York, NY, USA.
A. Nagy, P. Armatis, A.V. Schally, High yield conversion
of doxorubicin to 2-pyrrolinodoxorubicin, an analog
500-1000 times more potent: structure-activity
relationship of daunosamine-modified derivatives of
doxorubicin, Proceedings of the National Academy of
Sciences, 93 (1996) 2464-2469.
G. Rodriguez-Berna, M.J.D. Cabañas, V. MangasSanjuán,
M. Gonzalez-Alvarez, I. Gonzalez-Alvarez,
I. Abasolo, S. Schwartz Jr, M. Bermejo, A. Corma,
Semisynthesis, Cytotoxic Activity, and Oral Availability
of New Lipophilic 9-Substituted Camptothecin
Derivatives, ACS Med. Chem. Lett., 4 (2013) 651-655.
M.C. Wani, H.L. Taylor, M.E. Wall, P. Coggon, A.T.
McPhail, Plant antitumor agents. VI. Isolation and
structure of taxol, a novel antileukemic and antitumor
agent from Taxus brevifolia, J. Am. Chem. Soc., 93
(1971) 2325-2327.
P.B. Schiff, J. Fant, S.B. Horwitz, Promotion of
microtubule assembly in vitro by taxol, Nature, 277
(1979) 665-667.
D.B. Longley, D.P. Harkin, P.G. Johnston, 5-fluorouracil:
mechanisms of action and clinical strategies, Nature
reviews. Cancer, 3 (2003) 330-338.
B. Shi, B. Yaremko, G. Hajian, G. Terracina, W.R. Bishop,
M. Liu, L.L. Nielsen, The farnesyl protein transferase
inhibitor SCH66336 synergizes with taxanes in vitro
and enhances their antitumor activity in vivo, Cancer
Chemoth. Pharm., 46 (2000) 387-393.
O. Cuvillier, V. Nava, S. Murthy, L. Edsall, T. Levade,
S. Milstien, S. Spiegel, Sphingosine generation,
cytochrome C release, and activation of caspase-7
in doxorubicin-induced apoptosis of MCF7 breast
adenocarcinoma cells, Cell Death. Differ., 8 (2001)
162-171.
F.W. Symmans, Breast cancer response to paclitaxel
in vivo, Drug Resist. Update, 4 (2001) 297-302.
J. Wichmann, G. Adam, S. Kolczewski, V. Mutel,
T. Woltering, Structure-activity relationships of
substituted 5H-thiazolo[3,2-a]pyrimidines as group
2 metabotropic glutamate receptor antagonists,
Bioorg. Med. Chem. Lett., 9 (1999) 1573-157.
F.A. Al-Omary, G.S. Hassan, S.M. El-Messery, H.I. ElSubbagh,
Substituted thiazoles V. Synthesis and
antitumor activity of novel thiazolo[2,3-b]quinazoline
and pyrido[4,3-d] thiazolo[3,2-a] pyrimidine
analogues, Eur. J. Med. Chem., 47 (2012) 65-72.
S. Fatima, A. Sharma, R. Saxena, R. Tripathi, S.K.
Shukla, S.K. Pandey, R. Tripathi, R.P. Tripathi, One pot
efficient diversity oriented synthesis of polyfunctional
styryl thiazolopyrimidines and their bio-evaluation as
antimalarial and anti-HIV agents, Eur. J. Med. Chem.,
55 (2012) 195-204.
M. Yıldırım, D. Çelikel,Y. Dürüst, D.W. Knight, B.M.
Kariuki, A rapid and efficient protocol for the
synthesis of novel nitrothiazolo[3,2-c]pyrimidines
via microwave-mediated Mannich cyclisation,
Tetrahedron, 70 (2014) 2122-2128.
E. Flefel, M. Salama, M. El-Shahat, M. El-Hashash, A.
El-Farargy, A novel synthesis of some new pyrimidine
and thiazolopyrimidine derivatives for anticancer
evaluation, Phosphorus Sulfur., 182 (2007) 1739-1756.
R. Lin, S.G. Johnson, P.J. Connolly, S.K. Wetter, E.
Binnun, T.V. Hughes, W.V. Murray, N.B. Pandey, S.J.
Moreno-Mazza, M. Adams, Synthesis and evaluation
of 2,7-diamino-thiazolo[4,5-d]pyrimidine analogues
as anti-tumor epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitors, Bioorg. Med. Chem.
Lett., 19 (2009) 2333-2337.
B. Singh, S.K. Guru, S. Kour, S.K. Jain, R. Sharma,
P.R. Sharma, S.K. Singh, S. Bhushan, S.B. Bharate,
R.A. Vishwakarma, Synthesis, antiproliferative
and apoptosis-inducing activity of thiazolo[5,4-d]
pyrimidines, Eur. J. Med. Chem., 70 (2013) 864-874.
T.A.A. Yahya, J.H. Abdullah, M.A.H. Al-Ghorafi, S.H.
Yassin, H.M. Almahbshi, Synthesis of some arylidene
derivatives of thiazolopyrimidineas anticancer, Der
Pharma Chemica, 7 (2015) 106-110.
N.A. Abdel-Hafez, S.F. Mohamed, F.A. El-Hag, U.W.
Hawas, H.M. Awad, Synthesis and Cytotoxicity
Evaluation of Some New Pyrimidinethione
and Thiazolopyrimidine Derivatives Linked to
N-Propylpiperidone, Der Pharma Chemica, 8 (2016)
57-66.
B. Kuppast, H. Fahmy, Thiazolo[4,5-d]pyrimidines as
a privileged scaffold in drug discovery, Eur.J. Med.
Chem., 113 (2016) 198-213.
S. Kolb, O. Mondésert, M.L. Goddard, D. Jullien,
B.O. Villoutreix, B. Ducommun, C. Garbay, E. Braud,
Development of novel thiazolopyrimidines as CDC25B
phosphatase inhibitors, ChemMedChem, 4 (2009)
633-648.
A.A. Abu-Hashem, M.M. Youssef, H.A. Hussein,
Synthesis, antioxidant, antituomer activities of some
new thiazolopyrimidines, pyrrolothiazolopyrimidines
and triazolo pyrrolothiazolopyrimidines derivatives,
J.Chil. Chem. Soc., 58 (2011) 41-48.
M. Yıldırım, D. Çelikel, A rapid access to novel
and diverse 3-oxothiazolo[3,2-c]pyrimidine-8-
carboxylates using multicomponent Mannich
cyclisation reactions, Mol. Divers., 19 (2015) 1-13.
M. Stojanović, R. Marković, E. Kleinpeter, M. BaranacStojanović,
endo-Mode cyclizations of vinylogous
N-acyliminium ions as a route to the synthesis of
condensed thiazolidines, Tetrahedron, 67 (2011) 9541-
9554.
D. Çelikel, Synthesis of new thiazolopyrimidine,
thiazolo(imidazolo) pyridinone derivatives via
multicomponent reactions M.Sc. Master Thesis,
(2015) Abant İzzet Baysal University, Bolu,Turkey.
F.P. Karakas, A.B. Yildirim, R. Bayram, M.Z. Yavuz, A.
Gepdiremen, A.U. Turker, Antiproliferative activity
of some medicinal plants on human breast and
hepatocellular carcinoma cell lines and their phenolic
contents, Trop. J. Pharm. Res., 14 (2015) 1787-1795.
M.M. Kamel, H.I. Ali, M.M. Anwar, N.A. Mohamed,
A.M. Soliman, Synthesis, antitumor activity and
molecular docking study of novel sulfonamideSchiff’s
bases, thiazolidinones, benzothiazinones and
their C-nucleoside derivatives, Eur. J. Med. Chem., 45
(2010) 572-580.
X. Liu, W. Wei, S. Huang, S-S. Lin, X. Zhang, C. Zhang,
Y. Du, G. Ma, M. Li, S. Mann, Bio-inspired protein–
gold nanoconstruct with core–void–shell structure:
beyond a chemo drug carrier, J. Mater. Chem. B., 1
(2013) 3136-3143.
G.S. Hassan, Synthesis and antitumor activity
of certain new thiazolo[2,3-b]quinazoline and
thiazolo[3,2-a] pyrimidine analogs, Med. Chem. Res.,
23 (2014) 388-401.
L. Shen, J. Hu, H. Wang, A. Wang, Y. Lai, Y. Kang,
Synthesis and biological evaluation of novel uracil and
5-fluorouracil-1-yl acetic acid-colchicine conjugate,
Chem. Res. Chinese. U., 31(2015) 367-371.
P.N. Le, N.H. Nguyen, C.K. Nguyen, N.Q. Tran,
Smart dendrimer-based nanogel for enhancing
5-fluorouracil loading efficiency against MCF7 cancer
cell growth, B. Mater. Sci., 39 (2016) 1493-1500.
J.M. Gichumbi, B. Omondi, G. Lazarus, M. Singh,
N. Shaikh, H.Y. Chenia, H.B. Friedrich, Influence
of Halogen Substitution in the Ligand Sphere on
the Antitumor and Antibacterial Activity of Half
sandwich Ruthenium (II) Complexes [RuX( 6 arene)
(C5H4N2 CH=N Ar)]+, Z. Anorg. Allg. Chem., 643
(2017) 699-711.
I.M. Abbas, S.M. Gomha, M.M. Elaasser, B.K. Mabrouk,
Synthesis and characterisation of some novel fused
thiazolo[3,2-a]pyrimidinones and pyrimido[2,1-b][1,3]
thiazinones, J. Chem. Res., 39 (2015) 719-723.
S. Awad, O. Fathalla, J. Wietrzyk, M. Milczarek, A.
Soliman, M.S. Mohamed, Synthesis of new pyrimidine
derivatives and their antiproliferative activity
against selected human cancer cell lines, Res. Chem.
Intermediat., 41 (2015) 1789-1801.
S.M. Rida, S.A. El-Hawash, H.T. Fahmy, A.A. Hazza,
M.M. El-Meligy, Synthesis and in vitro evaluation of
some novel benzofuran derivatives as potential antiHIV-1,
anticancer, and antimicrobial agents, Arch.
Pharm. Res., 29 (2006) 16-25.
M.M. Mohamed, A.K. Khalil, E.M. Abbass, A.M. ElNaggar,
Design, Synthesis of New Pyrimidine
Derivatives as Anticancer and Antimicrobial Agents,
Synthetic Commun., 47 (2017) 1441-1457.
Year 2018,
Volume: 46 Issue: 2, 237 - 246, 03.06.2018
D. Peer, J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit,
R. Langer, Nanocarriers as an emerging platform for
cancer therapy, Nat. Nanotechnol., 2 (2007) 751-760.
F. Arcamone, Doxorubicin: anticancer antibiotics,
(2012) Elsevier, New York, NY, USA.
A. Nagy, P. Armatis, A.V. Schally, High yield conversion
of doxorubicin to 2-pyrrolinodoxorubicin, an analog
500-1000 times more potent: structure-activity
relationship of daunosamine-modified derivatives of
doxorubicin, Proceedings of the National Academy of
Sciences, 93 (1996) 2464-2469.
G. Rodriguez-Berna, M.J.D. Cabañas, V. MangasSanjuán,
M. Gonzalez-Alvarez, I. Gonzalez-Alvarez,
I. Abasolo, S. Schwartz Jr, M. Bermejo, A. Corma,
Semisynthesis, Cytotoxic Activity, and Oral Availability
of New Lipophilic 9-Substituted Camptothecin
Derivatives, ACS Med. Chem. Lett., 4 (2013) 651-655.
M.C. Wani, H.L. Taylor, M.E. Wall, P. Coggon, A.T.
McPhail, Plant antitumor agents. VI. Isolation and
structure of taxol, a novel antileukemic and antitumor
agent from Taxus brevifolia, J. Am. Chem. Soc., 93
(1971) 2325-2327.
P.B. Schiff, J. Fant, S.B. Horwitz, Promotion of
microtubule assembly in vitro by taxol, Nature, 277
(1979) 665-667.
D.B. Longley, D.P. Harkin, P.G. Johnston, 5-fluorouracil:
mechanisms of action and clinical strategies, Nature
reviews. Cancer, 3 (2003) 330-338.
B. Shi, B. Yaremko, G. Hajian, G. Terracina, W.R. Bishop,
M. Liu, L.L. Nielsen, The farnesyl protein transferase
inhibitor SCH66336 synergizes with taxanes in vitro
and enhances their antitumor activity in vivo, Cancer
Chemoth. Pharm., 46 (2000) 387-393.
O. Cuvillier, V. Nava, S. Murthy, L. Edsall, T. Levade,
S. Milstien, S. Spiegel, Sphingosine generation,
cytochrome C release, and activation of caspase-7
in doxorubicin-induced apoptosis of MCF7 breast
adenocarcinoma cells, Cell Death. Differ., 8 (2001)
162-171.
F.W. Symmans, Breast cancer response to paclitaxel
in vivo, Drug Resist. Update, 4 (2001) 297-302.
J. Wichmann, G. Adam, S. Kolczewski, V. Mutel,
T. Woltering, Structure-activity relationships of
substituted 5H-thiazolo[3,2-a]pyrimidines as group
2 metabotropic glutamate receptor antagonists,
Bioorg. Med. Chem. Lett., 9 (1999) 1573-157.
F.A. Al-Omary, G.S. Hassan, S.M. El-Messery, H.I. ElSubbagh,
Substituted thiazoles V. Synthesis and
antitumor activity of novel thiazolo[2,3-b]quinazoline
and pyrido[4,3-d] thiazolo[3,2-a] pyrimidine
analogues, Eur. J. Med. Chem., 47 (2012) 65-72.
S. Fatima, A. Sharma, R. Saxena, R. Tripathi, S.K.
Shukla, S.K. Pandey, R. Tripathi, R.P. Tripathi, One pot
efficient diversity oriented synthesis of polyfunctional
styryl thiazolopyrimidines and their bio-evaluation as
antimalarial and anti-HIV agents, Eur. J. Med. Chem.,
55 (2012) 195-204.
M. Yıldırım, D. Çelikel,Y. Dürüst, D.W. Knight, B.M.
Kariuki, A rapid and efficient protocol for the
synthesis of novel nitrothiazolo[3,2-c]pyrimidines
via microwave-mediated Mannich cyclisation,
Tetrahedron, 70 (2014) 2122-2128.
E. Flefel, M. Salama, M. El-Shahat, M. El-Hashash, A.
El-Farargy, A novel synthesis of some new pyrimidine
and thiazolopyrimidine derivatives for anticancer
evaluation, Phosphorus Sulfur., 182 (2007) 1739-1756.
R. Lin, S.G. Johnson, P.J. Connolly, S.K. Wetter, E.
Binnun, T.V. Hughes, W.V. Murray, N.B. Pandey, S.J.
Moreno-Mazza, M. Adams, Synthesis and evaluation
of 2,7-diamino-thiazolo[4,5-d]pyrimidine analogues
as anti-tumor epidermal growth factor receptor
(EGFR) tyrosine kinase inhibitors, Bioorg. Med. Chem.
Lett., 19 (2009) 2333-2337.
B. Singh, S.K. Guru, S. Kour, S.K. Jain, R. Sharma,
P.R. Sharma, S.K. Singh, S. Bhushan, S.B. Bharate,
R.A. Vishwakarma, Synthesis, antiproliferative
and apoptosis-inducing activity of thiazolo[5,4-d]
pyrimidines, Eur. J. Med. Chem., 70 (2013) 864-874.
T.A.A. Yahya, J.H. Abdullah, M.A.H. Al-Ghorafi, S.H.
Yassin, H.M. Almahbshi, Synthesis of some arylidene
derivatives of thiazolopyrimidineas anticancer, Der
Pharma Chemica, 7 (2015) 106-110.
N.A. Abdel-Hafez, S.F. Mohamed, F.A. El-Hag, U.W.
Hawas, H.M. Awad, Synthesis and Cytotoxicity
Evaluation of Some New Pyrimidinethione
and Thiazolopyrimidine Derivatives Linked to
N-Propylpiperidone, Der Pharma Chemica, 8 (2016)
57-66.
B. Kuppast, H. Fahmy, Thiazolo[4,5-d]pyrimidines as
a privileged scaffold in drug discovery, Eur.J. Med.
Chem., 113 (2016) 198-213.
S. Kolb, O. Mondésert, M.L. Goddard, D. Jullien,
B.O. Villoutreix, B. Ducommun, C. Garbay, E. Braud,
Development of novel thiazolopyrimidines as CDC25B
phosphatase inhibitors, ChemMedChem, 4 (2009)
633-648.
A.A. Abu-Hashem, M.M. Youssef, H.A. Hussein,
Synthesis, antioxidant, antituomer activities of some
new thiazolopyrimidines, pyrrolothiazolopyrimidines
and triazolo pyrrolothiazolopyrimidines derivatives,
J.Chil. Chem. Soc., 58 (2011) 41-48.
M. Yıldırım, D. Çelikel, A rapid access to novel
and diverse 3-oxothiazolo[3,2-c]pyrimidine-8-
carboxylates using multicomponent Mannich
cyclisation reactions, Mol. Divers., 19 (2015) 1-13.
M. Stojanović, R. Marković, E. Kleinpeter, M. BaranacStojanović,
endo-Mode cyclizations of vinylogous
N-acyliminium ions as a route to the synthesis of
condensed thiazolidines, Tetrahedron, 67 (2011) 9541-
9554.
D. Çelikel, Synthesis of new thiazolopyrimidine,
thiazolo(imidazolo) pyridinone derivatives via
multicomponent reactions M.Sc. Master Thesis,
(2015) Abant İzzet Baysal University, Bolu,Turkey.
F.P. Karakas, A.B. Yildirim, R. Bayram, M.Z. Yavuz, A.
Gepdiremen, A.U. Turker, Antiproliferative activity
of some medicinal plants on human breast and
hepatocellular carcinoma cell lines and their phenolic
contents, Trop. J. Pharm. Res., 14 (2015) 1787-1795.
M.M. Kamel, H.I. Ali, M.M. Anwar, N.A. Mohamed,
A.M. Soliman, Synthesis, antitumor activity and
molecular docking study of novel sulfonamideSchiff’s
bases, thiazolidinones, benzothiazinones and
their C-nucleoside derivatives, Eur. J. Med. Chem., 45
(2010) 572-580.
X. Liu, W. Wei, S. Huang, S-S. Lin, X. Zhang, C. Zhang,
Y. Du, G. Ma, M. Li, S. Mann, Bio-inspired protein–
gold nanoconstruct with core–void–shell structure:
beyond a chemo drug carrier, J. Mater. Chem. B., 1
(2013) 3136-3143.
G.S. Hassan, Synthesis and antitumor activity
of certain new thiazolo[2,3-b]quinazoline and
thiazolo[3,2-a] pyrimidine analogs, Med. Chem. Res.,
23 (2014) 388-401.
L. Shen, J. Hu, H. Wang, A. Wang, Y. Lai, Y. Kang,
Synthesis and biological evaluation of novel uracil and
5-fluorouracil-1-yl acetic acid-colchicine conjugate,
Chem. Res. Chinese. U., 31(2015) 367-371.
P.N. Le, N.H. Nguyen, C.K. Nguyen, N.Q. Tran,
Smart dendrimer-based nanogel for enhancing
5-fluorouracil loading efficiency against MCF7 cancer
cell growth, B. Mater. Sci., 39 (2016) 1493-1500.
J.M. Gichumbi, B. Omondi, G. Lazarus, M. Singh,
N. Shaikh, H.Y. Chenia, H.B. Friedrich, Influence
of Halogen Substitution in the Ligand Sphere on
the Antitumor and Antibacterial Activity of Half
sandwich Ruthenium (II) Complexes [RuX( 6 arene)
(C5H4N2 CH=N Ar)]+, Z. Anorg. Allg. Chem., 643
(2017) 699-711.
I.M. Abbas, S.M. Gomha, M.M. Elaasser, B.K. Mabrouk,
Synthesis and characterisation of some novel fused
thiazolo[3,2-a]pyrimidinones and pyrimido[2,1-b][1,3]
thiazinones, J. Chem. Res., 39 (2015) 719-723.
S. Awad, O. Fathalla, J. Wietrzyk, M. Milczarek, A.
Soliman, M.S. Mohamed, Synthesis of new pyrimidine
derivatives and their antiproliferative activity
against selected human cancer cell lines, Res. Chem.
Intermediat., 41 (2015) 1789-1801.
S.M. Rida, S.A. El-Hawash, H.T. Fahmy, A.A. Hazza,
M.M. El-Meligy, Synthesis and in vitro evaluation of
some novel benzofuran derivatives as potential antiHIV-1,
anticancer, and antimicrobial agents, Arch.
Pharm. Res., 29 (2006) 16-25.
M.M. Mohamed, A.K. Khalil, E.M. Abbass, A.M. ElNaggar,
Design, Synthesis of New Pyrimidine
Derivatives as Anticancer and Antimicrobial Agents,
Synthetic Commun., 47 (2017) 1441-1457.
Yıldırım, A. B., Mutlu, E., & Yıldırım, M. (2018). Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines. Hacettepe Journal of Biology and Chemistry, 46(2), 237-246.
AMA
Yıldırım AB, Mutlu E, Yıldırım M. Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines. HJBC. June 2018;46(2):237-246.
Chicago
Yıldırım, Arzu Birinci, Esra Mutlu, and Muhammet Yıldırım. “Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines”. Hacettepe Journal of Biology and Chemistry 46, no. 2 (June 2018): 237-46.
EndNote
Yıldırım AB, Mutlu E, Yıldırım M (June 1, 2018) Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines. Hacettepe Journal of Biology and Chemistry 46 2 237–246.
IEEE
A. B. Yıldırım, E. Mutlu, and M. Yıldırım, “Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines”, HJBC, vol. 46, no. 2, pp. 237–246, 2018.
ISNAD
Yıldırım, Arzu Birinci et al. “Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines”. Hacettepe Journal of Biology and Chemistry 46/2 (June 2018), 237-246.
JAMA
Yıldırım AB, Mutlu E, Yıldırım M. Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines. HJBC. 2018;46:237–246.
MLA
Yıldırım, Arzu Birinci et al. “Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines”. Hacettepe Journal of Biology and Chemistry, vol. 46, no. 2, 2018, pp. 237-46.
Vancouver
Yıldırım AB, Mutlu E, Yıldırım M. Cytotoxic Effects of Thiazolo[3,2-C]Pyrimidines Against Mcf-7 And Hepg2/C3a Carcinoma Cell Lines. HJBC. 2018;46(2):237-46.