Abstract
Two novel polyphosphoesters containing anthracene‐ and furan‐derived aminophosphonate moieties, namely, poly[oxyethylene(aminophosphonate‐co‐H‐phosphonate)]s P-12 and P-13, were synthesized through an addition of poly(oxyethylene H‐phosphonate) to 9‐anthrylidene‐furfurylamine and characterized. The novel polyphosphoester P-12 and a series of previously described anthracene‐derived compounds including Schiff bases S‐1 and S‐2, α‐aminophosphonates A-3–A-6, bis‐aminophosphonate B-6, two enantiomers A-5a and A-5b, and polyphosphoesters P-8–P-11 containing aminophosphonate units were screened for antitumor activity against a panel of human leukemic cell lines, using cisplatin as a reference cytotoxic agent. As concluded from the cytotoxicity assays, both precursors S-1 and S-2 presented similar cytotoxicity profiles that are cisplatin‐like only in the REH cell line. Leader compound of the α‐aminophosphonates is A-4 with cell death‐inducing properties fully equaling those of the referent drug in all of the screened leukemic cell lines with the only exception being the AML histological subtype HL‐60. Some of the polymeric analogues elicited moderate (P-10 and P-12) to low (P-11) cytotoxic activity, whereas the polyphosphoesters P-8 and P-9 produced in vitro antitumor effects largely surpassing cisplatin’s. The compounds P-8, P-9, and A-4 could be potential new materials for anticancer therapeutic purposed.
Highlights
Two novel polyphosphoesters containing anthracene- and furan-derived aminophosphonate moieties, namely, poly[oxyethylene]s P-12 and P-13, were synthesized through an addition of poly(oxyethylene H-phosphonate) to 9-anthrylidene-furfurylamine and characterized. e novel polyphosphoester P-12 and a series of previously described anthracene-derived compounds including Schiff bases S-1 and S-2, α-aminophosphonates A-3–A-6, bis-aminophosphonate B-6, two enantiomers A-5a and A-5b, and polyphosphoesters P-8–P-11 containing aminophosphonate units were screened for antitumor activity against a panel of human leukemic cell lines, using cisplatin as a reference cytotoxic agent
Poly[oxyethylene]s P-12 and P-13 (Scheme 1), which contain anthracene- and furan-derived aminophosphonate units, have been synthesized through an addition of poly(oxyethylene H-phosphonate) 1 to the Schiff base 9-anthrylidenefurfurylamine S-2. e polymer analogous reaction was carried out using an excess of the Schiff base and in the presence of CdI2 as a catalyst. e polymer P-12 was obtained in a good yield (69%) by conventional heating of the reagents at 60°C for 25 h. e preparation of the polymer P-13 was accomplished for a shorter reaction time (1 h) and in a higher yield (88%) with the assistance of microwave irradiation. e products P-12 and P-13 were obtained as viscous oils, soluble in common organic solvents and in water
E structure of the polyphosphoesters P-12 and P-13 was verified by means of IR and NMR spectral analysis. e IR spectra displayed absorption bands characteristic for stretching vibration of NH, PH, P O, and P-O-C groups. 1H NMR spectra of the products showed doublet signals at 5.68 and 5.71 ppm (P-12, in CDCl3 and in DMSO-d6, respectively) and 5.69 ppm (P-13, in CDCl3) with 2JPH about 23 Hz which can be assigned to the CHP proton from their units formed by addition reaction between the polymeric H-phosphonate and the Schiff base. e NH proton signal is masked in the spectra taken in CDCl3 solution
Summary
1H NMR spectra of the products showed doublet signals at 5.68 and 5.71 ppm (P-12, in CDCl3 and in DMSO-d6, respectively) and 5.69 ppm (P-13, in CDCl3) with 2JPH about 23 Hz which can be assigned to the CHP proton from their units formed by addition reaction between the polymeric H-phosphonate and the Schiff base. 31P{1H} NMR spectra of the products, taken in CDCl3 (P-12 and P-13) and DMSO-d6 (P-12) solutions, display a singlet signal about 25 ppm and another singlet in the range of 9.26–9.81 ppm, which are due to the phosphorus atoms of CHP and PH groups from the aminophosphonate and H-phosphonate repeating units, respectively. E racemic compound A-5, obtained from the anthracene- and furan-containing Schiff base S-2, appeared least effective in terms of growth inhibition, whereas both corresponding enantiomers (A-5a and A-5b) achieved markedly lower IC50 values, especially in the leukemic subtypes of lymphoid origin (SKW-3 and REH cells). Among the all tested compounds, we considered that aminophosphonate A-4 and, especially, polymers P-8 and P-9 appear very promising new materials for development of anticancer drugs
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