Calcareous sponges of the genus Leucetta are best known as sources of imidazole alkaloids.1 The exception is the pteridine alkaloid leucettidine (1), which was isolated from Leucetta microraphis from Bermuda.2 We recently reported the isolation of the zinc complex of clathridine ( 2) and (9E)-clathridine 9-JV-(2-sulfoethyl)imine (3) from a specimen of L. microraphis from Pohnpei.3 We have now investigated the chemistry of a maroon-colored calcareous sponge that, although quite different in physical appearance, was also identified as Leucetta microraphis.Antimicrobial screening of the crude methanolic extract of this sponge revealed mild activity against B. subtilis. A bioassay-guided fractionation using Sephadex LH-20, TSK 40s, and reversed-phase HPLC resulted in the isolation of leucettamole A (4) and B (5) as the active constituents.

Protein kinase C is physiologically activated by 1,2-diacyl-sn-glycerol in the S configuration. The enzyme is also powerfully activated by structurally diverse tumor promotors. A model has been developed that demonstrates how the various tumor promotors and diacylglycerols can all be accommodated by the same binding site of the kinase. One prediction of this model concerns the structural nature of the pharmacophore in the tumor promotor debromoaplysiatoxin. This prediction is realized by synthesizing the analogs with the deduced pharmacophore and demonstrating that they are potent activators of protein kinase C. These rindings provide strong experimental support for our structural model of protein kinase C activation.Protein kinase C (PKC) is an important regulatory enzyme involved in the control of diverse biological phenomena (1, 2). Under quiescent conditions, the enzyme is located in the cytoplasm, where it remains catalytically inactive (2). The enzyme is activated, in a transient fashion, when 1,2-diacylsn-glycerols in the S configuration are produced in the membrane by the action of a specific phospholipase C (2, 3). This latter enzyme cleaves inositol (poly)phospholipids to generate diacylglycerols and (poly)phosphoinositols (2, 4). The liberated diacylglycerol binds to the regulatory domain of PKC and activates PKC by increasing its affinity for calcium ions to the steady-state physiological range (2).The specificity of the activation process is considerable, with only a narrow range of unmodified diacylglycerols in the S configuration being active (5-9). We recently proposed (10) a structural hypothesis concerning the nature of the diacylglycerol-binding region in PKC. Our major concern was to resolve how the same effector binding site in PKC can specifically recognize both diacylglycerols and the structurally diverse tumor promotors (10-13). We proposed the structural correlation among PKC activators summarized in Fig. 1 (10). We have demonstrated (14) that PKC activation is also stereospecific with respect to the second chiral center of 3-methylated 1,2-diacyl-sn-glycerols. Furthermore, the absolute configuration at C2 and C3 of the active 3-methylated diacylglycerols is the same as the absolute configuration at C29 and C30 of the naturally occurring tumor promotor debromoaplysiatoxin (DAT) (Fig. 1) (10). These observations support our structural hypothesis and forge a structural link between tumor promotors and diacylglycerols for PKC activation. In this report, this structural link is further explored by synthesizing and testing two classes of the hybrids of diacylglycerols and aplysiatoxins. It is demonstrated that the structural predictions made by our hypothesis are realized in both classes of hybrids and that the 3,4-dihydroxybutyrate moiety found in aplysiatoxins is the minimally essential pharmacophore of this class of tumor promotors. MATERIALS AND METHODSMaterials. Bovine phosphatidylserine was obtained from Avanti Polar Lipids. 1,2-Dioleoyl-sn-glycerol and histone type VS were fr...