(Aminoalkyl)carbamates of forskolin: intermediates for the synthesis of functionalized derivatives of forskolin with different specificities for adenylyl cyclase and the glucose transporter

Abstract

(Aminoalkyl)carbamates of forskolin were synthesized at the 6- and 7-hydroxyl positions of forskolin with the length of the alkyl chain varying from ethyl to heptyl. Two of these derivatives, 7-[[(2-aminoethyl)amino]carbonyl]-7-desacetylforskolin (2) and 6-[[(2-aminoethyl)amino]carbonyl]forskolin (3), were used to synthesize iodinated derivatives of forskolin that bind with high affinity to adenylyl cyclase in bovine brain membranes and the glucose transporter in human erythrocyte membranes, respectively. Hydroxyphenyl derivatives of forskolin were prepared from the (aminoalkyl)carbamates and tested for their ability to bind to adenylyl cyclase in bovine brain membranes and the glucose transporter in human erythrocyte membranes. The 6-derivative (18) of forskolin had a Kd of 9 nM at adenylyl cyclase and was more potent than either the 7-derivatives or the 6-derivatives of 7-desacetylforskolin. The 7-derivatives were more potent at binding to the glucose transporter than forskolin. In contrast, the 6-derivatives had Kd's greater than 100 microM at the glucose transporter. Isothiocyanates and N-bromoacetyl derivatives were synthesized from 2 and 3 as potential alkylating agents for forskolin binding sites. The alkylating agents produced an irreversible loss of forskolin binding to adenylyl cyclase. In contrast, the alkylating agents bound reversibly to the glucose transporter.

High affinity regulation of cardiac Cl– and Ca2+ conductances by (13R)-spiroforskolin

“…Various forskolin derivatives have been synthesized and studied as activators of adenylyl cyclases (Seamon et al 1983;Seamon and Daly 1986;Laurenza et al 1987;Robbins et al 1991). So far, only a few of them have been tested as regulators of cardiac ionic conductances.…”

Kinetic and computational studies on aminolysis of bicyclic carbonates bearing alicyclic structure giving alicyclic hydroxyurethanes

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] The importance of the reactions is also emphasized by the improvement that cyclic carbonates can be prepared from carbon dioxide with safe and cost-effective procedures, [4][5][6][7][8][9][10][11][12][13][14][15][16] whereas carbonate synthesis had depended on highly toxic phosgene or its derivatives. [1][2][3] For instance, oxiranes and carbon dioxide react in the presence of catalysts (e.g., quaternary ammonium halides, alkali-metal halides, and transition metal compounds) to produce five-membered cyclic carbonates even under atmospheric pressure.…”

“…4 Even L-lysine inherently possessing a carboxyl group can be employed as a diamine. 5 In spite of the usefulness of aminolysis of cyclic carbonates, this reaction has been less applied for synthesis of alicyclic hydroxyurethanes, which are intermediates of biologically active compounds, [15][16][17][18] except for synthesis of forskolin derivatives. 15,16 Clarifying the aminolysis behavior of cyclic carbonates with alicyclic structure will be very informative in synthesis of alicyclic alcohols bearing urethane moieties as the protected alcohol groups.…”

“…5 In spite of the usefulness of aminolysis of cyclic carbonates, this reaction has been less applied for synthesis of alicyclic hydroxyurethanes, which are intermediates of biologically active compounds, [15][16][17][18] except for synthesis of forskolin derivatives. 15,16 Clarifying the aminolysis behavior of cyclic carbonates with alicyclic structure will be very informative in synthesis of alicyclic alcohols bearing urethane moieties as the protected alcohol groups. In addition, introduction of alicyclic structure to polymer backbone leads to higher thermal and optical properties, [19][20][21][22][23] therefore will afford poly(hydroxyurethane)s with improved properties.…”

Essential Role of Adenosine Triphosphate in Activation of 17β-Hydroxysteroid Dehydrogenase in the Rat Leydig Cell

“…Such findings raise the possibility that forskolin inhibition is related to its effect on glucose transporter(s) in the Leydig cell. Analogs of forskolin with selective specificity for the glucose transporter or adenylate cyclase, namely the naturally occurring analog 1,9-dideoxyforskolin (1, and the synthetic analog 6-aminoethyl carbamyl forskolin (6-AEC-F), respectively (2,11), were used in this study to elucidate the mechanism of forskolin's effect on steroidogenesis. Analogs of forskolin with selective specificity for the glucose transporter or adenylate cyclase, namely the naturally occurring analog 1,9-dideoxyforskolin (1, and the synthetic analog 6-aminoethyl carbamyl forskolin (6-AEC-F), respectively (2,11), were used in this study to elucidate the mechanism of forskolin's effect on steroidogenesis.…”