The synthesis and biological activity of two analogs of the anti‐HIV alkaloid michellamine B

Abstract

Two simplified analogs of the dimeric naphthalenyltetrahydroisoquinoline alkaloid michellamine B [4′,4″‐didesmethoxy‐2′,2″‐didesmethylmichellamine B and 6,8‐dihydroxy‐5‐(1′,1″‐dihydroxy‐2′,2″‐binaphthalen‐4′‐yl)‐1R,3R‐dimethyl‐1,2,3,4‐tetrahydroisoquinoline] were synthesized using Suzuki palladiumcatalyzed biaryl cross‐coupling of 4‐(2‐benzyl‐6,8‐dibenzyloxy‐1R,3R‐dimethyl‐1,2,3,4‐tetrahydroisoquinolin‐5‐yl)‐1‐benzyloxy‐2‐bromonaphthalene to its corresponding atropisomeric 2‐naphthaleneboronic acid and 1‐benzyloxy‐2‐naphthaleneboronic acid, respectively. These analogs inhibited recombinant HIV reverse transcriptase with IC5() values of 62 μM and 1000 μM, respectively, whereas the IC5() value for michellamine B was 33 μM. Both michellamine B and the analogs inhibited the phosphorylation of histories by rat brain protein kinase C. The analogs were more active (IC50 values of 36 μM and 30 μM, respectively) than michellamine B (IC50 = 130 μM).

Microwave-Assisted Solid-Liquid Phase Alkylation of Naphthols

“…In the first three cases, the alkylations were carried out using K 2 CO 3 /acetone or Cs 2 CO 3 /MeCN systems. The yields varied in the range of 39-98% (Table 1 / Entries 1-3) [18][19][20]. 2-Naphthol (6) was benzylated using a NaOH/PhMe system and a PT catalyst.…”

Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products

“…Recently, the first dimeric naphthylisoquinoline alkaloid from an Asian Ancistrocladaceae species, ancistrogriffithine A (11) (28), has been discovered using the novel LC-MS-NMR-CD 'triad' (28). By intermolecular coupling: first total synthesis of dioncophyllinc 8 (8) (937) the U.S. National Cancer Institute (951), several groups embarked on the total synthesis of michellamines, in particular michellamines A (lOa) and B (lOb) (939,945,(952)(953)(954) and their analogs (955)(956)(957). The michellamines are of interest not only for their structures (four stereocenters and three axes, two of which are stereogenic, while the central one can freely rotate, see Fig.…”

“…It is likewise the first dimer consisting of two 7 ,8' -coupled monomers. Key steps of the first syntheses were either the (biomimetic) chemical (942)(943)(944)(945)(946)(947)(948)(949)(950)(951)(952)(953)(954)(955)(956)(957)(958) or enzymic (959) oxidative dimerization of korupensamine derivatives to the corresponding michellamines (which, most recently, succeeded even without any protective groups) (960), alternatively, the double Suzuki coupling of a central binaphthalene fragment with two appropriately modified isoquinoline building blocks (961, 962). 79 Scheme 23.…”

β-Phenylethylamines and the isoquinoline alkaloids

“…4,4 -Didemethoxy-2,2 -didemethylmichellamine B 25, synthesised by processes analogous to the previously reported direct synthesis of michellamine, inhibits recombinant HIV reverse transcriptase at 60 g ml 1 . 26 The naphthyltin derivative 24 has been converted into 26a, and oxidation of the related phenol 26b gave a dimeric quinone, which was reduced to…”