Codeinone structure

The peptide sequences obtained for codeinone reductase aligned well with the amino acid sequences for 6 -deoxychalcone synthase (chalcone reductase) from alfalfa, Glycerrhiza, and soybean. Knowledge of the relative positions of the peptides allowed for a quick RT-PCR based isolation of cDNAs encoding codeinone reductase from P. somniferum. The codeinone reductase isoforms are 53 % identical to chalcone reductase from soybean.25 By sequence comparison, both codeinone reductase and chalcone reductase belong to the aldo/keto reductase family, a group of structurally and functionally related NADPH-dependent oxidoreductases, and thereby possibly arise from primary metabolism. Six alleles encoding codeinone... 

These data were used to good advantage in the structural elucidation of 10-oxocancentrine (44). Other physical data had suggested that the new alkaloid differed from cancentrine only at C-10. To provide additional support for these observations the 13C spectrum of 10-oxocancentrine and the model compounds, codeinone (45) and 10-oxocodeinone (46), were recorded. In the latter the carbonyl group at C-10 appears at 190.4 ppm. This change in functionality caused a deshielding of carbons C-9, C-14, C-3, and C-12 relative to codeinone. 

The other factor that may determine the type of cell death is the chemical structure of inducing agents [14]. We have recently found that u,(>-unsaluraled ketones such as 4,4-dimethyl-2-cyclopenten-l-one, a-methy-lene-y-butyrolactone, 5,6-dihydro-2H-pyran-2-one [15], codeinone [16], and morphinone [17] and a-hydroxylketones such as 3,3,3-trifluoro-2-hydroxy-1-phenyl-1-propanone induced caspase-independent cell death [18], induced vacuolization or autophagosome formation engulfing organelles, but without induction of apoptosis markers. 

Jacobson and others(390) analyzed the H-nmr spectra at 100 MHz of codeine and isocodeine derivatives, previously reported at 60 MHz,(391) in order to establish the conformation of the spiro-oxirane derived from codeinone.<200) Double irradiation and NOE experiments confirmed the structure illustrated (91). 

Reaction with Grignard Reagents Unlike codeinone i/r-codeinone readily reacts with methylmagnesium iodide, giving methyldihydro-i/r-codeinone, which is indifferent to liydrogenation and shows none of the properties of a ketone [7]. It has the structure [xxxi], analogous to that of phenyldihydrothebaine xxxn] [41-42], The mechanism of the production of these two bases is discussed in Chapter XX. 

The only recorded instance of the dehydration of a 14-hydroxy -codeinone derivative is that recorded by Schopf and Borkowsky, who claimed to have dehydrated 14-hydroxydihydrothebainone methine to [xxxvii] [34], Now [xxxvn] has the structure assigned to thebainone-B methine obtained by the hydrolysis of dihydrothebaine- methiodide [xxxvm] and /3-dihydrothebaine methine [xxxix] [35], and whereas thebainone-B methine can be hydrogenated to /3-dihydrothebainone... 

Propound modification of the structure, with migration of the basic side-chain and reversion to a fully aromatic phenanthrene derivative, occurs when thebaine [i] [1] or codeinone [n] [2] is heated with dilute hydrochloric acid, the product being the phenolic secondary amine thebenine [in], Triacetylthebenine is produced when -codeinone [iv] is heated with acetic anhydride [3], and thebenine-8-methyl ether (methebenine), 8-ethyl ether (ethebenine), and 8-propyl ether (prothe-benine) can be prepared by heating thebaine or codeinone with hydrochloric acid and methyl, ethyl, and propyl alcohol respectively [2, 4]. Methebenine, which can be hydrolysed to thebenine by hot 20 per cent, hydrochloric acid [4], is also obtained by the action of stannous chloride and acetic anhydride on thebaine [5]. 

We selected position 9 not only on the basis of the structural relation with isoquinoline alkaloids, but also because it was the only position that allowed us to give an explanation of the formation of thebenine (vi) from codeinone (vii). 

Scheme 1 Structures of morphine, codeine, thebaine, codeinone, and a morphine skeleton...

Buckett WR (1964) The relationship between analgesic activity, acute toxicity and chemical structure in esters of 14-hydroxy codeinone. J Pharm Pharmacol 16 68T-71T... 

Nieland NPR, Moynihan H, Carrington S, Broadbear J, Woods JH, Traynor JR, Husbands SM, Lewis JW (2006) Structural determinants of opioid activity in derivatives of 14-aminomorphinones effect of substitution in the aromatic ring of cinnamoylaminomorphinones and codeinones. J Med Chem 49 5333-5338... 

New Diels-Alder adducts of thebaine with aromatic nitroso-compounds of structure (118 R = H, Me, Cl) have been prepared. These are unstable and can be hydrolysed to 14-aryIhydroxylaminocodeinones (119), which can be reduced to derivatives of the hitherto inaccessible 14-aminodihydrocodeinone (120). The base (119 R = H) is susceptible to base-catalysed displacement of the oxide bridge, the product being the 5,14-bridged thebainone derivative (121). ° The reaction between thebaine and excess of ethyl azodicarboxylate involves Diels-Alder addition and addition of the N-CH3 group to a second molecule of azo-ester. The primary product (122) has not been isolated pure, but yields ethyl hydrazodicarboxylate and the substituted codeinone (123) on hydrolysis. ... 

Thebainone, 7,S-Didehydro-4-hydroxy-3-meth-oxy-l7-nteihvlmorphinan-6-one thebainone-A. C.gHj.NO, mol wt 299 36. C 72.21%, H 7.07%, N 4.68%, O 16.03%. Prepn from thebaine. codeinone Or 0-ethylthiocodide Morris, Small, J. Am. Chem. Soc. 56, 2159(1934). Earlier references and discussion of structure Small, Lutz, Chemistry of the Opium Alkaloids, U.S. Public Health Reports Suppt. No. 103, Washington (1932). About anomalies in nomenclature and difference from metathebaioone see Henry. Plant Alkaloids (London, 1939) p 249. Description of all thebainones K. W. Bentley, The Chemistry of I he Morphine Alkaloids (Oxford, 1954) p 219-... 

Several studies have reported the production in microorganisms of plant enzymes that are involved in alkaloid biosynthesis [29, 99-102], In this sense, Unterlinner et al. [100] have cloned and expressed in Escherichia coli four cDNAs encoding for different isoforms of the Codeinone reductase NADPH-dependent enzyme isolated from Papaver somniferum. In this report has been investigated the substrate specificity of the enzyme and the structural analysis, being the first report about the cloning and expression of genes of the biosynthetic pathway of morphine [90],... 

Horn JS, Paul AG, Rapoport H (1978) Biosynthetic conversion of thebaine to codeinone. Mechanism of ketone formation from enol ether in vivo. J Am Chem Soc 100 1895-1898 Kametani T, Ihara M, Honda T (1970) The alkaloids of Corydalis pallida var. tenuis (Yatabe) and the structures of pallidine and kikemanine. J Chem Soc (C) 1060—1064 Kirby GW, Massey SR, Steinreich P (1972) Biosynthesis of unnatural morphine derivatives in Papaver somniferum. J Chem Soc Perkin Trans 1 1642-1647 Kleinschmidt G, Mothes K (1959) Physiology and biosynthesis of alkaloids in Papaver somniferum. Z Naturforsch 14b 52-56... 

---