Zwitterionic Sulfobetaine Inhibitors of Squalene Synthase

Abstract

A substantial number of sulfobetaines (e.g., 10) have been synthesized and evaluated as inhibitors of squalene synthase (SS) on the basis of the idea that their zwitterionic structure would have properties conducive both to binding in the active site and to passage through cell membranes. When the simple sulfobetaine moiety is incorporated into compounds containing hydrophobic portions like those in farnesyl diphosphate (1) or presqualene diphosphate (2), inhibition of SS in a rat liver microsomal assay was indeed observed. For example, farnesylated sulfobetaine 10 has IC(50) = 10 &mgr;M and aromatic derivative 35 has IC(50) = 2 &mgr;M for SS inhibition. A wide variety of structural modifications, exemplified by compounds 43, 52, 76, 85, 91, 99, 111, and 115, was investigated. Unfortunately, no inhibitors in the submicromolar range were discovered, and exploration of a different type of zwitterion seems necessary if this appealing approach to inhibition of SS is going to provide a potential antihypercholesterolemic agent.

Structural relationships in small molecule interactions governing gas-phase enantioselectivity and zwitterionic formation

“…However, the unique interactions in cyclodextrin provide an environment that is capable of stabilizing the amino acids in the zwitterionic form. The intrinsic properties of zwitterionic amino acids are of fundamental interest as they affect the general properties of proteins [58,59].…”

Zwitterion formation in gas-phase cyclodextrin complexes

“…The resulting electric field plays a crucial role in determining the structure of many proteins and the reactivity enzymes [7][8][9]. Amino acids are known to exist as zwitterions in solution under appropriate pH conditions.…”

Synthesis of Sulfobetaines Based on Betulinic Acid and its Esters

“…They exhibited significantly higher antitumor and antimicrobial activity than the acid itself [6][7][8][9][10][11][12][13]. Sulfobetaine derivatives of betulinic acid and other lupane-type pentacyclic triterpenoids have not been reported despite the frequent use of the biomimetic sulfobetaine group to design biologically active compounds with antibacterial, antiviral, and antiproliferative properties; to increase the solubility of hydrophobic compounds; and also to construct nanocarriers for targeted drug delivery [14][15][16][17][18][19][20][21].New derivatives of betulinic acid (1) were prepared and their structure-biological-activity relationship was studied using the synthetic method developed by us for betulinic-acid sulfobetaines 2-4, a new class of lupane-type pentacyclic triterpenoids containing N,N-(dimethylammonium)butane-1-sulfonate bonded to the C-3 or C-28 position of the triterpene backbone.Sulfobetaines 2-4 were prepared by treating the corresponding triterpene C-3 or C-28 tertiary amine of 5-7 with commercially available 1,4-butane sultone [22,23]. Betulinic acid C-3 tertiary amine 5 was synthesized by acylating the C-3-OH of betulin 28-O-vinyl ether with chloroacetic acid (DCC, DMAP) and oxidizing in two steps the resulting betulin 3E-chloroacetate (9) with pyridinium chlorochromate (PCC) to give the corresponding aldehyde, which was reacted immediately after flash chromatography with NaClO 2 to obtain the 3E-chloroacetate of acid 10.…”

“…Sulfobetaines 2-4 were prepared by treating the corresponding triterpene C-3 or C-28 tertiary amine of 5-7 with commercially available 1,4-butane sultone [22,23]. Betulinic acid C-3 tertiary amine 5 was synthesized by acylating the C-3-OH of betulin 28-O-vinyl ether with chloroacetic acid (DCC, DMAP) and oxidizing in two steps the resulting betulin 3E-chloroacetate (9) with pyridinium chlorochromate (PCC) to give the corresponding aldehyde, which was reacted immediately after flash chromatography with NaClO 2 to obtain the 3E-chloroacetate of acid 10.…”