Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues

Abstract

A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50=8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45-58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45-73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1-19μM range.

Cycloaddition reactions for antiviral compounds

“…135 Another class of 1,3-dipole that found attention in the synthesis of nucleoside analogs is that of nitrile oxides. Isoxazolidines trans-293A and trans-293B exhibited the highest activity (EC 50 5 8.9 μM) toward cytomegalovirus.…”

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches

“…The third generation synthetic topo II inhibitor 9-aminoanthracycline derivative amrubicin ( 10 , SM-5887) has been shown to have comparable efficacy to doxorubicin in adult soft tissue sarcoma (STS) without obvious cardiac toxicity in a phase II study . Acting as DNA intercalators, two naphthalimide derivatives, amonafide ( 11 , AS1413) and mitonafide ( 14 , NSC 300288), have been studied in phase III and phase II clinical trials, respectively. , …”

“…30 derivatives, amonafide (11, AS1413) and mitonafide (14, NSC 300288), have been studied in phase III and phase II clinical trials, respectively. 31,32 Resistance to chemotherapeutic drugs has been a major obstacle in cancer chemotherapy. Most topo II poisons have frequently suffered from MDR, which is related to the overexpression of MDR-associated proteins (i.e., P-gp, MDR1, MRP1, and BCRP), resulting in enhanced efflux of chemotherapeutic drugs out of the cells.…”

Copper(i) complexes with quinolone appended 1,8-naphthalimide conjugates: structural characterization, DNA and protein binding and cytotoxicity studies

“…30,31 Naphthalimides with their unique photophysical properties such as large quantum yields, photostability and sizable Stokes shift, have been extensively used in both supramolecular and medicinal chemistry. 32 Naphthalimide exhibits a broad spectrum of biological applications such as antitumor activity which has been shown towards a variety of human and murine cells, 32 antibacterial, 33 antiviral, 34 analgesic, 35 antitrypanosomal, 36 etc. Apart from this, naphthalimide derivatives have been extensively utilized within non-biological applications such as optical brighteners, 37 fluorescent probes, 38 solar energy collectors 39 and laser dyes.…”