1,3-Diacylaminopropan-2-ols and Corresponding 2-Acyl Derivatives as Drug Carriers: Unexpected Pharmacological Properties

Abstract

The design of lipid vectors (pseudotriglycerides, PTGs), achieved by the amide isosteric substitution of the ester moieties of 1,3-diacylglycerols, is based on the structural similarity with natural triglycerides facilitating the passage of pharmacological agents across biological membranes. 2-S-Acetylthiorphan (hemiacetorphan) pseudotriglycerides, Z-glycine pseudotriglycerides and 1,3-diacylaminopropan-2-ols vector molecules differing by the nature of the acid side-chain are examined in acute toxicity, radioligand binding and guinea-pig ileum experiments. These evaluations have led us to distinguish two types of compounds. Linear derivatives, palmitoyl and decanoyl, are devoid of toxicity and intrinsic activity. Cyclic derivatives, which contain in the acyl chain a phenyl, cyclohexyl, cyclopentyl or adamantoyl ring, present additional properties. Cyclic derivatives of hemiacetorphan are lethal after intravenous administration. The mortality is governed by the 2-hemiacetorphan moiety in the cyclic vector molecules. Hemiacetorphan alone is also lethal. Cyclic vector molecules and related compounds inhibit the contractile response of the guinea-pig ileum induced by electrical stimulation, histamine or acetylcholine (noncompetitive antagonism) whereas linear entities and parent compounds are not active. In particular, the 2-hemiacetorphan 1,3-diadamantoylamide PTG presents pD'2 values 7.87 +/- 0.29 (vs histamine) and 7.97 +/- 0.12 (vs acetylcholine).

Synthesis, Optical Rotation, and Absolute Configurations of Santinols

“…They are known to be physiological effectors and endogenous vehicles for the transfer of essential fatty acids through the intestinal mucosa 1,2. These useful properties also make 1,3‐diacylglycerols valuable candidates for drug carriers3 and dietary/health supplements 4. In addition, 1,3‐diacylglycerols are apparent precursors to structured triacylglycerols.…”

Direct Acylation across a Silyloxy System of Glycerol with Carboxylic Acid Anhydrides: A Novel Strategy to the Prodrug Carrier Modules - 1,3-Diacyl-sn-glycerols

“…Biological importance of 1,3-diacyl-sn-glycerols (1, as physiological effectors 1 and endogenous vehicles for transporting essential fatty acids through intestinal mucosa, 2 made this class of biomolecules attractive candidates for rational design of target-specific drug carriers. 3 Along this line, symmetrical analogues of lipid mediators bearing at the C2-position antiinflammatory pharmaceuticals, 4 antioxidants, 5,6 anticancer, 7 or organ-addressed contrast agents, 8 have emerged as micromolecular vectors for directing therapeutics or requisite compounds to the metabolic pathways of natural lipids. In contrast to these, chemical and pharmacological potential of enantiomerically pure 1,3-DAG 9,10 has not been exploited to any significant extent, despite increasing need for this kind of compounds in the synthesis of structurally defined triacylglycerols, 11 enzymes substrates, 12 enzymes inhibitors, 13 or new surfactants useful in supramolecular chemistry.…”