Synthesis and antitumor activity of 3-[(methyl)bis(5-trialkylsilyl-furan-2-yl)silyl]propylamines

Abstract

Novel 3- [(methyl)bis(5-trialkylsilylfuran-2-yl) silyl]propylamines have been synthesized by a hydrosilylation reaction of aliphatic and heterocyclic N-allylamines in the presence of the Speier's catalyst. The effects of the structure of the amine and the alkyl substituent at the silicon atom on the cytotoxicity of the compounds have been studied.Heterocyclic amines are important structural fragments in many medicinal preparations [1,2]. Analysis of antitumor substances has shown that the introduction of a heterocyclic amino group leads to an increase in the solubility and the bioavailability of the active substance. This is seen for piperidine in Arzoxifene [3][4][5], Flavopiridol [6], and Perifosine [7-9], for morpholine in Canertinib [10, 11], Gefitinib [12-14], and Mofarotene [15], as well as for thiomorpholine in Prinomastat [16], piperazine in Dasatinib [17] and Imatinib [18, 19], and pyrrolidine in Idoxifene [20, 21].Previous studies have shown that hetarylaminoalkyl(siloxy)silanes which contain an alkyl(siloxy) group at the silicon atom possess antitumor, neurotropic, and bacteriostatic activity [22,23]. 2-(Aminopropyl)-dimethylsilyl-5-trialkylsilyl(germyl)furans also show a high cytotoxicity towards tumor cells [24,25].Bearing in mind literature information, an analysis of the fragments of known drugs, and also the fact that silylation of compounds increase their lipophilicity (and can even change the metabolism of a substance [26,27]) we decided to prepare a novel series of furylamines which contain, in a single molecule, two furan rings, a heterocyclic amine, and several silicon atoms and to study the cytotoxicity of the novel compounds obtained.The starting furylhydrosilanes 1 and 6 were prepared from furan by two consecutive organolithium syntheses (Scheme 1). Then smooth hydrosilylation of allylamines by hydrosilanes 1 and 6 was carried out when heated in the presence of the Speier's catalyst. This resulted in the preparation in good yields of a series of bis(furyl)silylamines 2-5 and 7-10 which contain two or three heterocycles and three silicon atoms in one molecule. The 13C and 29Si NMR data are given in Table 1. The silicon signals at lower fields (-3.5 to -11.0 ppm) are assigned to the silicon absorption in the trimethyl-and triethylsilyl substituents, and this agrees well

Synthesis and Cytotoxic Activity of 1‐{3‐[1‐(5‐Organylsilylfuran‐2‐yl)silinan‐1‐yl]propyl}amines and Some Trimethylgermyl Analogues

“…[4] On the other hand, heterocyclic amines are important structural fragments in many medicinal preparations. [5,6] The analysis of antitumor substances has shown that the introduction of a heterocyclic amino group leads to an increase in the solubility and the bioavailability of the active substance.Our previous investigations have demonstrated [7][8][9] that 3-[dimethyl(5-trialkylsilyl(gemyl)furan-2-yl)silyl]propylamines and 3-[(methyl)bis(5-trialkylsilylfuran-2-yl)silyl]propylamines possess promising cytotoxic activity accompanied by high toxicity and cytotoxicity to normal cells. To improve the cycloselectivity of this class of compounds and to reduce their toxcicity we decided to prepare a novel series of furylpropylamines, which contain a silacycle and an organosilicon or -germanium substituent in the furan ring in a single molecule and to study the cytotoxicity of the obtained compounds and estimate the effect of the silacycle, nature of the amine, and the type of element-organic substituent on the cytotoxicity.The starting 2-substituted furylhydrosilane 1 was prepared from furan by reaction with butyllithium, followed by addition of 1-chlorosilinane, 2,5-substituted furylhydrosilanes 2-5 have been prepared from substituted furans in a similar way.…”

“…Synthesis of 1-{3-[1-(5-organylsilylfuran-2-yl)silinan-1-yl]propyl}amines and some trimethylgermyl analogues.ethylsilyl substituents, and this agrees well with the silicon shifts in 2-trimethylsilylfuran (d = À11.5 ppm) [10] and 2-triethylsilylfuran (d = À3.6 ppm). [9] The higher field signals at d = À13.4 to À13.8 ppm and at d = À30.7 to À31.1 ppm are due to the resonance of the silicon atom in the silacycle in the furylpropylaminosilinanes (compounds 6-24) and hydrosilanes (compounds 1-5), correspondingly (see Table 3 in the Supporting Information).The cytotoxicity of amines 6--24 in vitro was investigated on two cell tumor lines, namely HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma), and normal mouse fibroblasts NIH 3T3 to determine the effect of silacyclization and the nature of the element-organic substituent in position 5 of the furan ring. Most of the studied compounds (9--22 and 24) exhibited high cytotoxic activity (IC 50 1-7 mg mL À1 ) in both cancer cells accompanied by high toxicity (LD 50 74-293 mg kg À1 ).…”

“…Our previous investigations have demonstrated [7][8][9] that 3-[dimethyl(5-trialkylsilyl(gemyl)furan-2-yl)silyl]propylamines and 3-[(methyl)bis(5-trialkylsilylfuran-2-yl)silyl]propylamines possess promising cytotoxic activity accompanied by high toxicity and cytotoxicity to normal cells. To improve the cycloselectivity of this class of compounds and to reduce their toxcicity we decided to prepare a novel series of furylpropylamines, which contain a silacycle and an organosilicon or -germanium substituent in the furan ring in a single molecule and to study the cytotoxicity of the obtained compounds and estimate the effect of the silacycle, nature of the amine, and the type of element-organic substituent on the cytotoxicity.…”

“…ethylsilyl substituents, and this agrees well with the silicon shifts in 2-trimethylsilylfuran (d = À11.5 ppm) [10] and 2-triethylsilylfuran (d = À3.6 ppm). [9] The higher field signals at d = À13.4 to À13.8 ppm and at d = À30.7 to À31.1 ppm are due to the resonance of the silicon atom in the silacycle in the furylpropylaminosilinanes (compounds 6-24) and hydrosilanes (compounds 1-5), correspondingly (see Table 3 in the Supporting Information).…”