Synthesis of dialkylaminoaryl phosphonate bioisosteres of tyrosine and tyramine: a novel application of allene phosphonate chemistry for the synthesis of false substrates of tyrosinase.
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Date
2015-11
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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 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-butenephosphonate
(3);diethyl 2-[2(4-hydroxyphenyl)ethylamino]-3-methyl-1-butenephosphonate (4);dimethyl 2-[2-(4-
hydroxyphenyl)ethylamino]-2-cyclohexyl-1-ethenephosphonate (5);diethyl 2-[2-(4-hydroxyphenyl)ethylamino]-
2-cyclohexyl-1-ethenephosphonate (6);diethyl 2-[2-(4-hydroxyphenyl)ethylamino]ethanephosphonate (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.
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Keywords
1, 2-Alkadienephosphonates, aminophenols, melanoma, tyramine, tyrosinase, melanin, melanogenesis, anagen hair pigmentation
Citation
Mazzuca Dean, Angelov Christo, Wiebe Leonard I. Synthesis of dialkylaminoaryl phosphonate bioisosteres of tyrosine and tyramine: a novel application of allene phosphonate chemistry for the synthesis of false substrates of tyrosinase. Journal of Applied Pharmaceutical Science. 2015 Nov; 5(11): 1-9.