A series of N6 substituted hydrazones derived from adenosine and 3'-C-methyladenosine (3'-MeAdo) was prepared in search for potential novel antitumor agents. The stereochemistry of these compounds was established by means of NMR spectroscopy and the antiproliferative activity was determined in a panel of human tumor cell lines in vitro. INTRODUCTION, RESULTS AND DISCUSSION, CONCLUSION Despite recent progress in tumor therapy, the majority of solid tumors are currently not curable by chemotherapy. Half of all cancer patients fail to respond to chemotherapy or relapse from the initial response and ultimately die from their metastatic disease. Recently, the clinical outcome of cancer patients has improved dramatically with combination chemotherapy, and today anticancer research is centering on developing targeted and individualized therapies. Even so, current treatments often do not completely rid patients of their cancers and cancer cells can become resistant to various chemotherapeutic agents directed at them. Thus significant challenges remain and there is the urgency to develop novel chemotherapeutic agents for treatment of some cancer types that can become refractory and/or show little responsiveness to current chemotherapy (e.g., colon, prostate, ovarian, and renal cancer, non-small cell lung carcinoma, CNS cancers, and melanoma). Ribonucleotide reductase (RR), a critical enzyme for the synthesis of deoxyribonucleotides and cell division, is over-expressed in rapidly dividing cancer cells, making it an im-portant target for cancer therapy. Recently, we reported that 3'-C-methyladenosine (3'-MeAdo) is a mechanism-based RR inhibitor endowed with a significant antitumor activity against a panel of human leukemia and carcinoma cell lines [1,2]. Among the N6-modified adenosine analogues, 6-hydrazinopurine-riboside has recently been reported by us to be a potent mutagenic agent acting as inhibitor of human RR, possibly by scavenging tyrosyl free radicals involved in the reduction of nucleoside diphosphates [3]. We now report on the synthesis and antitumor activity of a series of adenosine and 3'-C-methyladenosine derivatives substituted at N6 with methyl and pyridyl hydrazones. The stereochemistry of these compounds was established to be E by means of NMR spectroscopy. The antiproliferative activity of the substituted purine nucleosides against a panel of human tumor cell lines will be presented. REFERENCES 1. Franchetti, P., Cappellacci, L., Pasqualini, M., Petrelli, R., Vita, P., Jayaram, H.N., Horvath, Z., Szekeres, T., Grifantini, M. J. Med. Chem. 2005, 48, 4983-4989. 2. Cappellacci, L., Franchetti, P., Vita, P., Petrelli, R., Lavecchia, A., Jayaram, H.N., Saiko, P., Graser,G., Szekeres, T., Grifantini M. J. Med. Chem. 2008, 51, 4260-4269. 3. Cappellacci, L., Petrelli, R., Franchetti, P., Vita, P., Kusumanchi, P., Kumar, M., Jayaram, H.N., Zhou, B., Yun Yen, Y., Grifantini, M. Eur. J. Med. Chem. 2011, 46, 1499-1504.

SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF NOVEL HYDRAZONE DERIVATIVES

PETRELLI, Riccardo;TORQUATI, ILARIA;FRANCHETTI, Palmarisa;GRIFANTINI, Mario;CAPPELLACCI, Loredana
2014-01-01

Abstract

A series of N6 substituted hydrazones derived from adenosine and 3'-C-methyladenosine (3'-MeAdo) was prepared in search for potential novel antitumor agents. The stereochemistry of these compounds was established by means of NMR spectroscopy and the antiproliferative activity was determined in a panel of human tumor cell lines in vitro. INTRODUCTION, RESULTS AND DISCUSSION, CONCLUSION Despite recent progress in tumor therapy, the majority of solid tumors are currently not curable by chemotherapy. Half of all cancer patients fail to respond to chemotherapy or relapse from the initial response and ultimately die from their metastatic disease. Recently, the clinical outcome of cancer patients has improved dramatically with combination chemotherapy, and today anticancer research is centering on developing targeted and individualized therapies. Even so, current treatments often do not completely rid patients of their cancers and cancer cells can become resistant to various chemotherapeutic agents directed at them. Thus significant challenges remain and there is the urgency to develop novel chemotherapeutic agents for treatment of some cancer types that can become refractory and/or show little responsiveness to current chemotherapy (e.g., colon, prostate, ovarian, and renal cancer, non-small cell lung carcinoma, CNS cancers, and melanoma). Ribonucleotide reductase (RR), a critical enzyme for the synthesis of deoxyribonucleotides and cell division, is over-expressed in rapidly dividing cancer cells, making it an im-portant target for cancer therapy. Recently, we reported that 3'-C-methyladenosine (3'-MeAdo) is a mechanism-based RR inhibitor endowed with a significant antitumor activity against a panel of human leukemia and carcinoma cell lines [1,2]. Among the N6-modified adenosine analogues, 6-hydrazinopurine-riboside has recently been reported by us to be a potent mutagenic agent acting as inhibitor of human RR, possibly by scavenging tyrosyl free radicals involved in the reduction of nucleoside diphosphates [3]. We now report on the synthesis and antitumor activity of a series of adenosine and 3'-C-methyladenosine derivatives substituted at N6 with methyl and pyridyl hydrazones. The stereochemistry of these compounds was established to be E by means of NMR spectroscopy. The antiproliferative activity of the substituted purine nucleosides against a panel of human tumor cell lines will be presented. REFERENCES 1. Franchetti, P., Cappellacci, L., Pasqualini, M., Petrelli, R., Vita, P., Jayaram, H.N., Horvath, Z., Szekeres, T., Grifantini, M. J. Med. Chem. 2005, 48, 4983-4989. 2. Cappellacci, L., Franchetti, P., Vita, P., Petrelli, R., Lavecchia, A., Jayaram, H.N., Saiko, P., Graser,G., Szekeres, T., Grifantini M. J. Med. Chem. 2008, 51, 4260-4269. 3. Cappellacci, L., Petrelli, R., Franchetti, P., Vita, P., Kusumanchi, P., Kumar, M., Jayaram, H.N., Zhou, B., Yun Yen, Y., Grifantini, M. Eur. J. Med. Chem. 2011, 46, 1499-1504.
2014
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/335582
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