Abstract
Tyrosinase is the rate-limiting oxidase in the synthesis of melanin, making it an obvious target for the treatment of melanotic melanomas. Tyrosine and tyramine are its natural substrates, but many of their derivatives are inhibitors or false substrates, and are therefore prime candidates for melanoma chemotherapy. A series of dialkylphosphonate derivatives of tyramine have now been synthesized in order to extend the chemical diversity of tyrosinase substrates. The known reactivity between alkenephosphonates and nucleophiles was exploited by the addition of 4-(2-aminoethyl)phenol (tyramine) across the 2,3-double bond of dialkyl 1,2-alkadiene phosphonates, to obtain the desired bisphosphonate derivatives. These reactions were highly chemoselective and regioselective but not stereoselective. Five of the reported novel dialkylphosphonate aminophenols were substrates for mushroom tyrosinase in vitro: dimethyl 2-[2(4-hydroxyphenyl)ethylamino]-3-methyl-1-butene phosphonate (3); diethyl 2-[2(4-hydroxyphenyl)ethylamino]-3-methyl-1-butene phosphonate (4); dimethyl 2-[2-(4-hydroxyphenyl)ethylamino]-2-cyclohexyl-1-ethene phosphonate (5); diethyl 2-[2-(4-hydroxyphenyl)ethylamino]-2-cyclohexyl-1-ethene phosphonate (6); diethyl 2-[2-(4-hydroxyphenyl)ethylamino]ethane phosphonate (7). Compound 3 blocked the pigmentation of anagen hair in vivo in a murine animal model, a further demonstration that these compounds are able to enter and disrupt the melanogenic pathway.
Highlights
Malignant melanoma is among the most aggressive and drug resistant cancers
A series of dialkylphosphonate derivatives of tyramine have been synthesized in order to extend the chemical diversity of tyrosinase substrates
The known reactivity between alkenephosphonates and nucleophiles was exploited by the addition of 4-(2-aminoethyl)phenol across the 2,3-double bond of 1,2-alkadiene phosphonates, to obtain the desired bisphosphonate derivatives
Summary
Malignant melanoma is among the most aggressive and drug resistant cancers It arises via a poorly understood interplay of host-environment interactions and risk factors. Reaction of amines at the 1,2-double bond of dialkyl butadienephosphonates to form the respective 1,2-adducts. Nucleophilic addition of amines at the 2,3 double bond of dialkyl butadienephosphonates to form the respective 2,3-adducts (Palacios et al, 1996). The first example of the reaction of amines with substituted allenephosphonic acid derivatives was published in 1966 (Pudovik and Khusainova, 1966) when it was shown that diethylamine and piperidine add to dialkyl 3-methyl-1,2-butadienephosphonates on the -double bond to afford 1,2-aducts (Scheme 1). The current work is based on the premise that incorporation of phosphonate moieties into the alkylamino portion of the tyrosinase substrates could potentially open the door to novel antimelanotic compounds through changes in target enzyme selectivity, pharmacokinetics, target-selective delivery and processing along the melanogenic pathway. The design and synthesis of several structural phosphonate analogues of tyrosine is reported, along with preliminary evidence for their oxidation by tyrosinase and their inhibition of melanogenesis
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