Facile separation and mild acidic hydrolysis of the diastereomeric amides derived from 2-methyl-4-hexenoic acid and L-2-phenylglycinol are used in a rapid, preparative-scale synthesis of (2R,4E)-2-methyl-4-hexenal, a key intermediate of MeBmt.
Steroselective Alkylation at C(α) of Serine, Clyceric Acid, Threonine, and Tartaric Acid Involving Heterocyclic Enolates with Evocyelic Double Bonds The chiral, non‐racemic title acids are converted to methyl dioxolane‐( cf. 13 ), oxazoline‐( 4 ) and oxazolidinecarboxylates ( cf. 9 ). Deprotonation by Li(i‐Pr) 2 N at dry‐ice temperature gives solutions of the lithium enolates A–D With exocyclic enolate double bonds. These are stable crough with respect to β‐elimination ( Scheme 1 ) to be alkylated with or without cosolvents such as HMPA or DMPU The products are formed in good to excellent yields and, with the exception of the tartrate‐derived acetonlde ( see Scheme 2 ), with diastereoselectivities above 90%. While the tartrate‐and threonine‐derived enolates ( A and B , resp.) are chiral due to the second stereogenic center of the precursors, the serine‐ and glyceric‐acid‐derived enolates ( A and B , resp.) are chiral due to the second sterogenic center of the precursors, the serine‐nd glyceric‐acid‐derived enolates are non‐racemic due to a tert butyl‐substituted (pivalaldehyde‐derived) acetal center ( C and D , resp.). The products of alkylation can be hydrolyzed to give α‐branched tartaric acid ( Scheme 2 ), allothreonine ( Scheme 3 ), serine ( Scheme 4 ), and glyceric‐acid derivatives ( Scheme 5 ) with quaternary stereogenic centers. The configurations of the products are determined by NOE‐NMR measurements and by chemical correlation. These show that the dioxolane‐derived enolates A and D are alkylated preferentially from that face of the ring which is already substituted (‘ syn ’‐attack), while the dihydrooxazol‐and oxazolidine‐derived enolates B and C are alkylated from the opposite face (‘ anti ’‐attack). The ‘ syn ’‐attack is postulated to arise from strong folding of the heterocyclic ring due to electronic repulsion between the enolate π‐system and non‐bonding electron pairs on the heteroatoms ( see Scheme 6 ).
Using X-ray structure-based de novo design, a new class of inhibitors of the zinc-dependent endopeptidase Neprilysin has been developed that feature binding affinities (IC50 values) in the upper nanomolar range. The imidazole moieties of the central benzimidazole or imidazo[4,5-c]pyridine (see picture) scaffolds act as efficient peptide-bond isosters.
Abstract Diastereoselective α‐alkylation of β‐hydroxycarboxylic esters through alkoxide enolates: diethyl (2 S , 3 R )‐( + )‐3‐allyl‐2‐hydroxysuccinate from diethyl ( S )‐( − )‐malate reactant: 9.51 g (50 mmol) of ( − )‐diethyl ( S )‐malate product: allylated product product: (2 S ,3 R )‐3‐allyl‐2‐hydroxysuccinic acid
2,30xidosqualene :lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug.Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the production of epoxysterols that repress HMGCoA reductase expression, generating a synergistic, self-limited negative regulatory loop.Hence, the pharmacological properties of Ro 488071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin.Ro 48-8071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the production of monooxidosqualene, dioxidosqualene, and epoxycholesterol.It was safe in hamsters, squirrel monkeys and a ttingen minipigs at pharmacologically active doses, lowering LDL -60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simvastatin.The latter was hepatotoxic in hamsters at doses >30 pmol/kg/day limiting its window of efficacy.Hepatic monooxidosqualene increased dose-dependently after treatment with Ro 488071, up to -20 pg/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels.Ro 48-8071 did not reduce coenzyme Q l O levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene synthase, and OSC itself.In strong contrast, simvastatin stimulated these enzymes dramatically, and reduced coenzyme Q l O levels in liver and h e a r t .I Altogether these findings clearly differentiate the OSC inhibitor Ro 488071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.-
Endothelin-1 (ET-1) is mitogenic and/or antiapoptotic in human cancers, and antagonists to ET-1 receptors are under evaluation for cancer treatment. Inhibition of ET-1 activation by the endothelin-converting enzymes 1a-d (ECE-1a-d; EC 3.4.24.71) represents another approach to block the ET-1 effect in cancer. To evaluate this potential, we synthesized and characterized a series of low nanomolar nonpeptidic thiol-containing ECE-1 inhibitors, and evaluated their effect, as well as the effect of inhibitors for the related metalloproteases neprilysin (NEP; EC 3.4.24.11) and angiotensin-converting enzyme (ACE; EC 3.4.15.1), on human glioblastoma cell growth. Only ECE-1 inhibitors inhibited DNA synthesis by human glioblastoma cells. Exogenous addition of ET-1 or bigET-1 to glioblastoma cells did not counterbalance the growth inhibition elicited by ECE-1 inhibitors, suggesting that ECE-1 inhibitors block the proliferation of human glioblastoma cells most likely via a mechanism not involving extracellular production of ET-1. This class of molecules may thus represent novel therapeutic agents for the potential treatment of human cancer.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)