Phosphatidylinositol mannoside ether analogues: syntheses and interleukin-12-inducing properties

Phosphatidylinositol mannosides (PIMs) isolated from mycobacteria have been identified as an important class of glycolipids with significant immune modulating properties. We present here the syntheses of phosphatidylinositol dimannoside ether analogues 2 and 3 and evaluate their interleukin-12 (IL-12)-inducing properties along with dipalmitoyl PIM2 (1) in an in vitro bovine dendritic cell assay. Both synthetic PIM analogues and synthetic dipalmitoyl PIM2 (1) were effective at enhancing IL-12 production by immature bovine dendritic cells. Unexpectedly, ether analogue 2 was significantly more active than dipalmitoyl PIM2 (1) which indicates that modified PIM compounds can be strongly immunoactive and may have significant adjuvant activities.     

Total Asymmetric Synthesis of a New 9,12‐Anhydroerythronolide Aglycone

Two novel, potentially antimicrobial erythronolide aglycon analogs ((−)‐ 9 and (−)‐ 30 , respectively), which incorporate a large number of contiguous stereogenic centers, have been prepared by multistep synthesis from simple chirons. The chemistry presented demonstrates the power of the so‐called ‘naked sugars of the second generation' approach. As for the sporeamicins, our macrolides are 9,12‐anhydroerythronolides, yet presenting a higher degree of complexity due to additional functional groups.     

Chemical synthesis and immunosuppressive activity of dipalmitoyl phosphatidylinositol hexamannoside

Phosphatidylinositol mannosides (PIMs) isolated from mycobacteria have been identified as an important class of phosphoglycolipids with significant immune-modulating properties. We present here the synthesis of dipalmitoyl phosphatidylinositol hexamannoside (PIM(6)) 1 and the first reported functional biology of a synthetic PIM(6). Key steps in the synthetic protocol included the selective glycosylation of an inositol 2,6-diol with a suitably protected mannosyl donor and construction of the glycan core utilizing a [3 + 4] thio-glycosylation strategy. The target 1 was purified by reverse phase chromatography and characterized by standard spectroscopic methods, HPLC, and chemical modification by deacylation to dPIM(6). The (1)H NMR spectrum of synthetic dPIM(6) obtained from 1 matched that of dPIM(6) obtained from nature. PIM(6) (1) exhibited dendritic cell-dependent suppression of CD8(+) T cell expansion in a human mixed lymphocyte reaction consistent with the well established immunosuppressive activity of whole mycobacteria.     

Hodgsonox, a new class of sesquiterpene from the liverwort Lepidolaena hodgsoniae. Isolation directed by insecticidal activity

Hodgsonox (1), a new insecticidal sesquiterpene, has been isolated from the New Zealand liverwort Lepidolaena hodgsoniae. The structure was elucidated on the basis of 2D NMR analysis of 1 and a synthetic epoxide derivative (2). Hodgsonox represents a new class of sesquiterpene with a cyclopenta[5,1-c]pyran ring system fused to an oxirane ring. The combination of a mono- and a 1,1 disubstituted double bond flanking the oxygenated carbon of a the pyran ring is a unique structural feature. Hodgsonox is toxic to larvae of the blowfly Lucilia cuprina.     

A parallel multi-configuration self-consistent field algorithm

A scalable multi-configuration self-consistent field (MCSCF) algorithm is described. The method for optimizing the orbital and configurational parameters is based upon the two-step Newton–Raphson approach with an augmented orbital Hessian matrix. A single copy of the two-electron integrals in the molecular orbital basis is distributed over the memory of all processors. Storage of the augmented Hessian is avoided by re-computing its elements as needed. A replicated data approach is used to parallelize the configuration interaction step. Scalability to 1024 processors is demonstrated.     

Synthesis and structure of phosphatidylinositol dimannoside

(R)-tuberculostearic acid (2) was synthesized in seven steps from (S)-citronellol (5). The carbon chain of 2 was assembled by copper-catalyzed cross coupling of (S)-citronellol tosylate (6) and hexylmagnesium bromide; subsequent ozonolysis and reaction with 6-benzyloxyhexylmagnesium bromide furnished alcohol 10. Functional group manipulation afforded (R)-2 in 49% overall yield from 5. DCC coupling of (R)-2 with 3-O-benzyl-1-O-palmitoyl-sn-glycerol (16), followed by hydrogenolytic removal of the benzyl group and treatment with benzyl bis(diisopropyl)phosphoramidite, afforded phosphoramidite 20. Tetrazole-mediated coupling of 20 with PIM1 head group 21 gave 22, and subsequent debenzylation afforded phosphatidylinositol mono-mannoside, PIM1 (23). Similarly, coupling of 20 and 24 and removal of the benzyl protecting groups gave PIM2 (1c). Both 23 and 1c have a clearly defined acylation pattern, which was confirmed by mass spectrometry, with sn-1 palmitoyl and sn-2 tuberculostearoyl groups on the glycerol moiety. Both 23 and 1c were shown to modulate the release of the pro-inflammatory cytokine, IL-12, in a dendritic cell assay.