The synthesis and reactivity of [N(8)-C(3')]-cyclized bicyclomycin. Evidence of the role of the C(1)-triol group in bicyclomycin-mediated processes

Abstract

5223in context with the biosynthetic studies on the kinamyc i n~~~ and on metabolites of the toromycin/gilvocarcin group (e.g., chrysomycin B33) an angucyclinone-type intermediate was proven and assumed, respectively, which undergoes a rearrangement leading to the found structures. Thus, a strong similarity of the polyketide synthases of (32) Seaton, P. J.; Gould, S. J. J. Am. Chem. SOC. 1987, 109, (33) Carter, G. T.; Fantini, A. A.; James, J. C.; Borders, D. B.; White, 5282-5284. R. J. J. Antibiot. 1983, 38, 242-248. these antibiotic groups with the angucycline-PKS is or seems to be evident.Such similarities of the polyketides synthases may have implications in future biosynthetic studies on the different types of multicyclic polyketides which cannot be carried out without the tools of genetic engineering and/or mutagenesis. This also justifies further biosynthetic studies on the angucyclines, which will be focused on in early biosynthetic step, since these may be also relevant for the clinically important tetracyclines and anthracyclines.The C(1) triol group in the antibiotic, bicyclomycin (1) has been proposed to play an integral role in the bonding of key protein nucleophiles to the distal C (5)-C(5a) terminal double bond in the drug. Evidence in support of this concept has been provided by the comparison of the reactivities of bicyclomycin (l), the [N(d)-C(B')]-cyclized bicyclomycin adduct 3, 2',3'-bicyclomycin acetonide (17), and the acetonide derivative of 3, 18, with sodium ethanethiolate. Significantly, 3 displayed enhanced reactivity versus 1, 17, and 18 in this transformation. The controlling factors for the increased reactivity of 3 have been discerned and the importance of the C(1') hydroxyl group delineated. Key kinetic parameters are reported for the treatment of both 3 and 17 with 2-mercaptopyridine. Structural details are provided for both C(5a) thiolate and amine adducts of 3. The importance of these findings in relation to the mode of action of bicyclomycin are briefly discussed. (10) (a) Williams, R. M.; Tomizawa, K.; h t r o n g , R. W.; Dung, J.-S. The following uninverted Chemical Abstracts Index name for 3 modified by current IUPAC guidelines has been kindly provided by Dr. P. M. Giles (Chemical Abstract Services): (5R,SR,lOS,lOaS)-hexahydro-5,9,10-trihydroxy-9-methyl-4-methylene-8~-5,lOa-(iminomethano)-6H-pyrrolo [ 2,lb] [ 1,3] oxazocine-6,1 l-dione. 8-10,20,24, and 27 importance of the C(1) triol moiety in activating the distal exomethylene group in bicyclomycin at moderate "pH" values. RCHg k-u s 2 Q 9 248 2z RH --OMS 2 3 X-Y-OH U X,Y = OC(CH&O Scheme I. Potential Pathways for the Formation of Compounds Results and DiscussionOur studies began with the observation that treatment of the known bicyclomycin-3'-0-methanesulfonateg (4) with 2 equiv of the heterocyclic amines, morpholine (5), Nacetylpiperazine (6), and N-methylpiperazine (71, led to the efficient production of 8-10, respectively.12 Inspection of the 'H and '3c NMR spectra for these adducts indicated that functionaliza...

α-Hydroxyhippuric Acid Derivatives: Ph-Dependent Aqueous Kinetics And Buffer Catalysis.

“…[13][14][15][16][17][18][19][20][21] Further evidence suggested that 2 covalently attaches, however, the nature of this covalent modification and mechanism by which it occurs has not been determined. 7 The outcome described above couples well with potential modes of reactivity that were observed in previous studies that investigated the reactivity of bicyclomycin at a variety of pH values in the presence of nucleophiles (Scheme 2). One study, which was performed in 3:1 THF/H 2 O in the presence of thiolate nucleophiles, proposed a mode of bioactivity based upon the products of the reaction isolated and identified.…”

“…been shown to be important intermediates in a variety of biological venues and critical to the bioactivity of a number of compounds. [2][3][4][5][6][7][8][9][10][11][12] One area where a carbinolamide has been found to have an interesting role is in the commercially available antibiotic bicyclomycin (2). Bicyclomycin is not a broad spectrum antibiotic but it has been shown to inhibit the growth of gram-negative bacteria.…”

“…Bicyclomycin is not a broad spectrum antibiotic but it has been shown to inhibit the growth of gram-negative bacteria. [2][3][4][5][6][7][8][9][10][11][12] This particular antibiotic is thought to have a unique form of reactivity due to the bioactivity of the critical carbinolamide functional group (highlighted in blue, see 2). site for ATP hydrolysis.…”

“…Scheme 2 shows the proposed mechanism for the reaction of 2 in the presence of thiolate nucleophiles that was used to explain the outcome of the reaction. 7 The proposed mechanism has the carbinolamide reversibly opening to unmask an α,β-unsaturated ketone. Once unmasked, the α,β-unsaturated ketone would be susceptible to nucleophilic attack and covalent modification (see Scheme 2).…”

“…Of particular interest was the discovery that carbinolamides are essential intermediates (7) for enzymatic synthesis of peptide hormones. Peptidylglycine α-6 !…”