Yehiel Gaoni’s research while affiliated with Weizmann Institute of Science and other places

Four novel 2,4-methano amino acids (MAAs, 1-aminocyclobutane-1-carboxylic acids) were synthesized. These include the basic MAA analogs of lysine (16), ornithine (5), and arginine (6) and the neutral methanovaline (22), related to proline. The above MAAs, as well as the MAA analog of homothreonine (7), were incorporated into the peptide chain of the immunomodulatory peptide tuftsin, Thr-Lys-Pro-Arg, known to enhance several biological activities mediated by phagocytic cells. The synthetic methano tuftsin analogs were assayed for their ability to stimulate interleukin-6 (IL-6) secretion by mouse peritoneal macrophages and for their stability in human serum toward enzymatic degradation. It was found that, at 2 x 10(-7) M, [MThr1]tuftsin (24) and an isomer of [MVal3]tuftsin (27a) were considerably more active than the parent peptide in augmentation of cytokine release. [MOrn2]Tuftsin (25) was equally potent. The analogs [MThr1]tuftsin (24) and [MOrn2]tuftsin (25), both pertaining to the proteolytically sensitive Thr-Lys bond of tuftsin, exhibited high resistance to enzymatic hydrolysis as compared to tuftsin. Using specific rabbit anti-tuftsin antibodies in a competitive enzyme-linked immunosorbent assay (ELISA) revealed that none of the MAA analogs can cross-react with tuftsin. It may indicate that the peptides assume global structures different than that of tuftsin.

A range of cis- and trans-3-substituted 1-aminocyclobutane-1-carboxylic acids has been synthesized and evaluated for antagonism at excitatory amino acid receptor sites and for anticonvulsant activity. Potent and selective antagonist activity at N-methyl-D-aspartate (NMDA) receptor sites in neonatal rat motoneurones was shown by compounds in which the 3-substituent was, or contained, a 2'-carboxyethyl or 2'-phosphonoethyl moiety. Substances 4b, 24, 35, and 40 were more potent than the standard NMDA receptor antagonist, D-2-amino-5-phosphonopentanoate (D-AP5) as NMDA antagonists in this preparation, and about equipotent with [3-(+/-)-2-carboxypiperazin-4-yl)-1-propyl]phosphonate (CPP). Anticonvulsant activity, as assessed following intracerebroventricular injection into audiogenic DBA/2 mice, generally paralleled NMDA receptor antagonist activity.

Cis- and trans-2,4-methanoglutamate were compared with L-glutamate as acidic amino acid ligands. Cis-2,4-methanoglutamate had a Ki of 0.052 μM against N-methyl-D-aspartate (NMDA)-specific L-[3H]glutamate binding compared with 0.050 μM for L-glutamate. Cis-2,4-methanoglutamate exhibited no significant affinity against [3H]kainate or [3H]α-amino-3-hydroxy-5-methyl-4-isoxazole propionate ([3H]AMPA) binding. Trans-2,4-methanoglutamate had no significant affinity for any of these sites. Cis-2,4-methanoglutamate increased [3H]N-1[2-thienyl]cyclohexyl-3, 4-piperidine ([3H]TCP) binding with EC50 of 0.35 ± 0.14 μM. It produced an inward current in rat brain mRNA-injected Xenopus oocytes which was blocked by the NMDA antagonist, D-2-amino-7-phosphonoheptanoate (D-AP7). Cis-2,4-methanoglutamate (EC50 = 15.9 μM) was 100-fold more potent than L-glutamate (EC50 = 1,584 μM) in reducing the excitatory postsynaptic potential in CA1 of hippocampal slices. Cis-2,4-methanoglutamate is the most potent, selective NMDA agonist known.

In view of planned syntheses of target cyclobutane derivatives, a series of new 3-substituted bicyclobutanes was prepared from sulfones 1–7. Some novel addition reactions involving the central bond were then applied to several of the new compounds as well as to some previously described bicyclobutanes. These reactions include the additions of hydrazoic acid, of cyanocuprate reagents other than methyl reagents, and of phenylselenol, as well as single examples of addition of phenylselenyl azide and of lithium bromide. Several 3-allylated bicyclobutane derivatives were transformed into 1-(arylsulfonyl)bicyclo[2.1.1]hexanes by conversion to cyclobutanes, epoxidation and intramolecular base-induced cyclization.

Addition of hydrazoic acid or benzylamine to 1-(arylsulfonyl) bicyclobutanes introduces the nitrogen nucleophlle at position 3 of the derived cyclobutane, even when a carboxyl derivative is present at this position as a second activating group. Precursors of α-amino cyclobutane carboxylic acids may thus be obtained and these can be further transformed to the title diacids via carbonylation α to the sulfone and reduction.

Methylierungsreaktionen an den Bicyclobutan-sulfonen (I) werden untersucht, deren Herstellung z.Tl. in der angegebenen Weise beschrieben wird.

Addition of methylmagnesium iodide /cuprous iodide or of lithium dimethylcuprate to 2-exo- and 2-endomethyl-1-(phenylsulfonyl)bicyclo[l.l.O]butane and determination of the relative geometry of the methyls in the 2,3-dimethylcyclobutaneso btained allowed us to establish that addition of the methyl group occurred from the endo side of the bicyclic molecule. Similarly, lithium aluminum hydride reduction of 2-exo,3- and 2-endo,3-dimethylbicyclobutane was also found to occur by endo-addition of the hydride ion at position 3 of the bicyclic system.