TY - JOUR
T1 - Synthesis, structure andin vitroantiproliferative effects of alkyne-linked 1,2,4-thiadiazole hybrids including erlotinib- And ferrocene-containing derivatives
AU - Boulhaoua, Mohammed
AU - Pasinszki, Tibor
AU - Torvisco, Ana
AU - Oláh-Szabó, Rita
AU - Bősze, Szilvia
AU - Csámpai, Antal
N1 - Funding Information:
We thank Dr Gerald Draeger (Institute of Organic Chemistry, Leibniz University Hannover, Germany) for recording and analysing HR-MS data. We also thank the Hungarian Research Fund (OTKA; grant no. 129037) for supporting this research.
Publisher Copyright:
© The Royal Society of Chemistry 2021.
PY - 2021/8/15
Y1 - 2021/8/15
N2 - Chemotherapy is an indispensable tool to treat cancer, therefore, the development of new drugs that can treat cancer with minimal side effects and lead to more favorable prognoses is of crucial importance. A series of eleven novel 1,2,4-thiadiazoles bearing erlotinib (a known anticancer agent), phenylethynyl, ferrocenyl, and/or ferrocenethynyl moieties were synthesized in this work and characterized by NMR, IR and mass spectroscopies. The solid-phase structures were determined by single-crystal X-ray diffraction. Partial isomerisation of bis(erlotinib)-1,2,4-thiadiazole into its 1,3,4-thiadiazole isomer, leading to the isolation of a 3 : 2 isomer mixture, was observed and a plausible mechanism for isomerisation is suggested. Thein vitrocytostatic effect and the long-term cytotoxicity of these thiadiazole-hybrids, as well as that of erlotinib, 3,5-dichloro-1,2,4-thiadiazole and 3,5-diiodo-1,2,4-thiadiazole were investigated against A2058 human melanoma, HepG2 human hepatocellular carcinoma, U87 human glioma, A431 human epidermoid carcinoma, and PC-3 human prostatic adenocarcinoma cell lines. Interestingly, erlotinib did not exhibit a significant cytostatic effect against these cancer cell lines. 1,2,4-Thiadiazole hybrids bearing one erlotinib moiety or both an iodine and a ferrocenethynyl group, as well as 3,5-diiodo-1,2,4-thiadiazole demonstrated good to moderate cytostatic effects. Among the synthesized 1,2,4-thiadiazole hybrids, the isomer mixture of bis-erlotinib substituted 1,2,4- and 1,3,4-thiadiazoles showed the most potent activity. This isomer mixture was proven to be the most effective in long-term cytotoxicity, too. 3,5-Diiodo-1,2,4-thiadiazole and its hybrid with one erlotinib fragment were also highly active against A431 and PC-3 proliferation. These novel compounds may serve as new leads for further study of their antiproliferative properties.
AB - Chemotherapy is an indispensable tool to treat cancer, therefore, the development of new drugs that can treat cancer with minimal side effects and lead to more favorable prognoses is of crucial importance. A series of eleven novel 1,2,4-thiadiazoles bearing erlotinib (a known anticancer agent), phenylethynyl, ferrocenyl, and/or ferrocenethynyl moieties were synthesized in this work and characterized by NMR, IR and mass spectroscopies. The solid-phase structures were determined by single-crystal X-ray diffraction. Partial isomerisation of bis(erlotinib)-1,2,4-thiadiazole into its 1,3,4-thiadiazole isomer, leading to the isolation of a 3 : 2 isomer mixture, was observed and a plausible mechanism for isomerisation is suggested. Thein vitrocytostatic effect and the long-term cytotoxicity of these thiadiazole-hybrids, as well as that of erlotinib, 3,5-dichloro-1,2,4-thiadiazole and 3,5-diiodo-1,2,4-thiadiazole were investigated against A2058 human melanoma, HepG2 human hepatocellular carcinoma, U87 human glioma, A431 human epidermoid carcinoma, and PC-3 human prostatic adenocarcinoma cell lines. Interestingly, erlotinib did not exhibit a significant cytostatic effect against these cancer cell lines. 1,2,4-Thiadiazole hybrids bearing one erlotinib moiety or both an iodine and a ferrocenethynyl group, as well as 3,5-diiodo-1,2,4-thiadiazole demonstrated good to moderate cytostatic effects. Among the synthesized 1,2,4-thiadiazole hybrids, the isomer mixture of bis-erlotinib substituted 1,2,4- and 1,3,4-thiadiazoles showed the most potent activity. This isomer mixture was proven to be the most effective in long-term cytotoxicity, too. 3,5-Diiodo-1,2,4-thiadiazole and its hybrid with one erlotinib fragment were also highly active against A431 and PC-3 proliferation. These novel compounds may serve as new leads for further study of their antiproliferative properties.
UR - http://www.scopus.com/inward/record.url?scp=85115196152&partnerID=8YFLogxK
U2 - 10.1039/d1ra05095h
DO - 10.1039/d1ra05095h
M3 - Article
AN - SCOPUS:85115196152
SN - 2046-2069
VL - 11
SP - 28685
EP - 28697
JO - RSC Advances
JF - RSC Advances
IS - 46
ER -