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R. C. Schoenfeld et al. / Bioorg. Med. Chem. Lett. 12 (2002) 823–825
large scale (Scheme 1). Reaction of N-acetyl-3,5-
dibromo-4-hydroxy-b-phenethylamine 510 with 3-bromo-
propylphthalimide, potassium carbonate, and catalytic
potassium iodide in acetonitrile at reflux smoothly
afforded protected diamine 6 in 98% yield. Exhaustive
hydrolysis with concentrated HCl at reflux furnished
moloka’iamine 1 as its dihydrochloride salt. The ethyl and
n-butyl analogues 7 and 8 were prepared in similar fashion.
aminopropylated and deprotected as described above in
the synthesis of 1 to give the unhalogenated and chlori-
nated analogues 13 and 14, respectively.
Initially, 1 and its analogues 7, 8, 13, and 14 were
assayed against B. amphitrite using a previously descri-
bed cyprid settlement assay (Table 1).12 The weak
activity observed with 13 and 14 indicated that bro-
mines were strictly required for antifouling perfor-
mance. The most active compound tested was the ethyl
analogue 7.
N-Acetyltyramine 911 was used as starting material for
the synthesis of additional analogues (Scheme 2).
Chlorination of 9 with sulfuryl chloride in ether affor-
ded 10 in modest yield. Phenols 9 and 10 were then
Noting the increased activity associated with a shorter
alkyl chain, we decided to investigate the naturally-
occurring bromotyramine 2, in which a methyl group
replaces the aminopropyl chain found in 1. Compound
2, first synthesized in 1958 as part of a veterinary clinical
study10 and more recently isolated from an Eudistoma
sp. Ascidian,7 was found to be the most potent anti-
fouling bromotyramine reported to date, a full two
orders of magnitude more active than 1.
Bromotyramines 15 and 16 were designed to hybridize
the aromatic portion of 2 with the aliphatic portion of
an antifouling natural product such as ceratinamide B
(4, IC50=2.4 mg/mL vs B. amphitrite),6 having a long-
chain alkyl group appended to the phenethylamine
nitrogen. We reasoned that a more lipophilic version of
2 would be more soluble in a coating, and therefore
more practical as an antifouling paint additive. Acet-
ylation of 2 with octanoyl chloride afforded amide 15 in
near-quantitative yield (Scheme 3). Reduction of 15
with borane-THF, followed by an acidic workup, furn-
ished octylamine 16 as its HCl salt. Compounds 15 and
16 strongly inhibited the settlement of barnacle cyprids,
with IC50 values of 0.2 and 0.008 mg/mL, respectively. It
Scheme 1. Reagents and conditions: (a) PhthN(CH2)3Br, K2CO3, KI,
acetonitrile, reflux, 98%; (b) concd HCl, reflux, 84%.
Scheme 2. Reagents and conditions: (a) SO2Cl2, diethyl ether, 38%;
(b) PhthN(CH2)3Br, K2CO3, KI, acetonitrile, reflux, 87–98%; (c)
concd HCl, reflux, 21–86%.
Scheme 3. Reagents and conditions: (a) C7H15COCl, triethylamine,
methylene chloride, 99%; (b) BH3-THF, 98%.
Table 2. Growth inhibition of human cancer cell lines by selected
bromotyramine compounds (1, 2, 3, 5, 7, 8, 13, 14, 15, and 16) at 10 0
mM
Table 1. Antifouling activity of bromotyramine natural products (1
and 2) and their analogues (7–8 and 13–16) against barnacle Balanus
amphitrite
% Growth
Compd
Settlement inhibition EC50
(mg/mL)
Lethality LD50
(mg/mL)a
Compd
NCI-H460(lung)
MCF-7 (breast)
SF-268 (CNS)
1
2
3a
5
7
8
13
14
15
16
68
53
82
105
7039
25
12010120
93
38
8
7
88
70
19
62
16
39
84
1
2
7
8
13
14
15
16
5.0nt
0.07
0.8
0.2
nt
6.0nt
>50nt
33
50
nt
1.0
0.03
4
0.2
0.008
À53
À74
À82
85
À68
À84
1
À83
nt, not tested.
aConcentrations at which the compounds tested were lethal to 50% of
the barnacle cyprids.
aCompound 3 (ceratinamine) was synthesized as described previously.9