Synthesis and biological activity of new 2-[(3-aminopropyl)dimethyl-silyl]-5-trialkylgermylfurans

Abstract

New highly cytotoxic 3-aminopropyl derivatives of 2-dimethylsilyl-5-trialkylgermylfuran (IC 50 1−3 µg⋅ml −1 ) have been prepared by hydrosilylation of heterocyclic N-allylamines with the corresponding hydrosilane in the presence of Speier's catalyst. The influence of the amine structure and alkyl substituent at the germanium atom on the cytotoxicity has been investigated.The heterocyclic amines are important building blocks for the creation of anticancer drugs [1, 2]. In some cases the benzene ring has been substituted for thiophene or furan to enhance the activity and increase the therapeutic index. Examples are the thiophene-containing folate analogue Raltitrexed [3], the antimetastatic agent Batimastat [4], and the furan-containing anticancer agent Lapatinib [5].Our previous investigations have demonstrated that hetarylaminoalkyl(siloxy)silanes, containing an alkyl(or siloxy) group attached to the silicon atom, have anticancer, neurotropic, and bacteriostatic activity [6−8]. On the other hand, toxicological studies have demonstrated that most tested organogermanium compounds were less toxic than the corresponding organosilicon analogs [9].Taking into consideration the information gained from the fragment analysis of known anticancer drugs as well as the fact that silylation and germylation increase the lypophilicity of the compounds and can change their metabolism [10−12] we decided to combine in one molecule the fragments of germylated furan and silylated heterocyclic amine and to test their cytotoxicity.The starting 2-dimethylsilyl-5-trimethyl(ethyl)germylfurans 1 and 12 have been prepared from the furan by two consecutive organolithium syntheses. These compounds were used for the hydrosilylation of heterocyclic allylamines in the presence of Speier's catalyst (Scheme 1). Hydrosilylation of all studied

Synthesis, structure and cytotoxicity of new 2‐[(3‐aminopropyl)dimethylsilyl]‐5‐furfural diethylacetals and 2‐[(3‐aminopropyl)dimethylsilyl]‐5‐phenylfurans

“…Silylpropylamino derivatives of diethoxymethylfuran 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 have a certain cytoselectivity: compounds of this type exhibited high cytotoxicity to MG‐22 tumor cell lines (compounds 9 and 12 are an exception) and at the same time they were less toxic to HT‐1080. It should be noted that compounds with the phenyl substituent in position 5 of the furan ring generally have more pronounced cytotoxic activity on tumor cell lines compared to the analogues with Et 3 Si group and Et 3 Ge group in the furan ring . Morpholino derivative 19 is the more promising compound among the studied amines: moderate toxicity (LD 50 659 mg kg −1 ), high cytotoxicity on both cancer cell lines (IC 50 1–3 µg ml −1 ) and low cytotoxicity on normal fibroblasts (IC 50 60 µg ml −1 ).…”

“…Previously we studied the synthesis and cytotoxic activity of 2‐[(3‐aminopropyl)‐dimethylsilyl]‐5‐trialkylsilyl(germyl)furans . Our investigations have demonstrated that these types of compounds have high cytotoxic activity on two cell tumor lines, viz.…”

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.…”

“…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.…”

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

“…2-(Aminopropyl)-dimethylsilyl-5-trialkylsilyl(germyl)furans also show a high cytotoxicity towards tumor cells [24,25].…”