ABCD Fragment Research Articles

Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer

Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer

Synthetic Approach to the ABCD Ring System of Anticancer Agent Fredericamycin A via Claisen Rearrangement and Ring-Closing Metathesis as Key Steps.

A new synthetic strategy to the ABCD ring system of the anticancer agent fredericamycin A (NSC-305263) was realized by the Diels–Alder reaction and olefin metathesis as key steps. The tactics developed here for the construction of the ABCD ring system also involve double Claisen rearrangement followed by a retro-Diels–Alder reaction and ring-closing metathesis. The metathesis approach performs a key role in the construction of A and D rings of the ABCD core unit. More importantly, ABCD fragment synthesis was accomplished without the involvement of protecting groups.

Synthesis of the ABCD fragment of gymnocin-B

A convergent synthesis of the ABCD fragment of gymnocin-B was accomplished. The tetracyclic ether ring system was synthesized by the construction of the BC ring system via the oxiranyl anion alkylation and ring expansion reaction, followed by the formation of the five-membered A-ring via a stereoselective radical cyclization reaction of a neopentyl-type iodide.

The structural modeling of EF-hand motifs in parvalbumin

Parvalbumin (Parv) is a typical protein with EF-hand motifs that play an important role in many physiological processes. We present a novel free energy to model the skeletal C $$_\alpha $$ chain of the protein from the basic principle of mathematics and physics. Starting from the crystal structure of Parv (PDB code 2PVB), we first analyze the profile of the C $$_\alpha $$ bond and torsion angles over the segment that contains the secondary structures. Then the parameters in the energy function are evaluated for the helix ABCD fragment that contains two EF-hand domains in Parv. Meanwhile an eight-soliton configuration at the energy minimum is constructed to model the conformation of ABCD fragment. The deviation of the conformation constructed from the model away from the crystal structure is as small as 1.28 A. The structural modeling stems from the physical energy, which is a benefit relative to the statistics-based or knowledge-based technologies.

Total Synthesis of (+)‐Azaspiracid‐1. Part I: Synthesis of the Fully Elaborated ABCD Aldehyde

Has aspirations: The total synthesis of (+)-azaspiracid-1 has been realized. The ABCD fragment was synthesized in 20 linear steps and 16 % overall yield through the enantioselective syntheses of the AB sulfone and the CD aldehyde, their coupling by a sulfone anion addition, and a thermodynamically controlled bis(spiroketalization) event. The E, FG, and HI ring fragments were synthesized enantioselectively and then coupled by using aldol methodology. Finally, a complex addition of the anion of the anomeric EFGHI sulfone to the ABCD aldehyde completed the synthesis in 26 linear steps and 2.7 % yield. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z701515_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Synthesis of New Camptothecin Analogues with the E‐Lactone Ring Replaced by α,β‐Cyclohexenone

AbstractThe total synthesis of racemic camptothecin analogues 12a and 12b, in which the E‐lactone ring has been replaced by an α,β‐cyclohexenone ring and the ethyl and hydroxy substituents have been retained, was achieved by first preparing the ABCD fragments 31a and 31b, which were then converted into the tetracyclic triol 36a and 36b by osmium‐mediated dihydroxylation. Compounds 36a and 36b were oxidized in one‐pot reactions, followed by intramolecular aldol condensation to furnish the desired pentacyclic 12a and 12b, which retained topoisomerase I inhibitory activity and exhibited cytotoxicity to tumor cell growth in culture.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

MDR Reversal by Deprenylated Tetracyclic and Hexacyclic Analogues of N-Acetylardeemin: Confirmation of the Ardeemin Pharmacophore

The MDR chemosensitising activity of several analogues of the ardeemins, including five derivatives of the ABCD fragment, nine derivatives of the complete hexacyclic framework and one seco analogue lacking the B ring was studied. The results obtained confirm that the pharmacophoric moiety of the ardeemins as MDR reversers is located at their DEF fragment, and suggest that the epimer of the ardeemins at the alanine stereocenter should be more active than the natural stereoisomer. Keywords: Antitumour drug resistance, MDR, glycoprotein P-170, ardeemin, pharmacophore

Second‐Generation Total Synthesis of Azaspiracids‐1, ‐2, and ‐3

The naturally occurring but scarce marine neurotoxins azaspiracids-1, -2, and -3 have been synthesized from five key building blocks by a convergent strategy that involved dithiane and Stille coupling reactions. The ABCD fragments were constructed through a cascade reaction involving deprotection/self-assembly of the precursors, while the FGHI fragment was forged by a neodymium triflate-induced cyclization. The final ring closure (ring G) was achieved, after the union of all fragments, through an iodoetherification reaction followed by reductive removal of the facilitating iodine residue. These improved, second-generation routes confirm the absolute structures and render all three azaspiracids readily available for biological studies.

Structural revision and total synthesis of azaspiracid-1, part 2: definition of the ABCD domain and total synthesis.

Structural revision and total synthesis of azaspiracid-1, part 2: definition of the ABCD domain and total synthesis.

Synthesis of the C‐1—C‐28 ABCD Unit of Spongistatin 1.

The synthesis of the C-1−C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1−C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key β-keto-dithiane unit required for the synthesis of the AB spiroketal fragment.

Synthesis of the C-1-C-28 ABCD unit of spongistatin 1.

The synthesis of the C-1-C-28 ABCD fragment of spongistatin is described. Anti-selective boron-mediated aldol coupling of a CD spiroketal ketone fragment to an AB spiroketal aldehyde unit forms the desired C1-C28 advanced intermediate. Other features include the double conjugate addition of a dithiol to an ynone to generate the key beta-keto-dithiane unit required for the synthesis of the AB spiroketal fragment. [reaction: see text]

Molecular Dynamics Study of Ca2+ Binding Loop Variants of Silver Hake Parvalbumin with Aspartic Acid at the “Gateway” Position

The helix-loop-helix (i.e., EF-hand) Ca2+ ion binding motif is characteristic of a large family of high-affinity calcium ion binding proteins, including the parvalbumins, oncomodulins and calmodulins. In this work we describe a set of molecular dynamics computations on the major parvalbumin from the silver hake (SHPV-B) and on functional fragments of this protein, consisting of the first four helical regions (the ABCD fragment), and the internal helix- loop-helix region (the CD fragment). In both whole protein and protein fragments (i.e., ABCD and CD fragments), the 9th loop residue in the calcium ion binding site in the CD helix-loop-helix region (the so-called “gateway” position) has been mutated from glutamic acid to aspartic acid. Aspartic acid is one of the most common residues found at the gateway position in other (non-parvalbumin) EF-hand proteins, but has never been found at the gateway position of any parvalbumin. (Interestingly, aspartic acid does occur at the gateway position in the closely related rat and human oncomodulins.) Consistent with experimental observations, the results of our molecular dynamics simulations show that incorporation of aspartic acid at the gateway position is very disruptive to the structural integrity of the calcium ion coordination site in the whole protein. The aspartic acid mutation is somewhat less disruptive to the calcium ion coordination sites in the two parvalbumin fragments (i.e., the ABCD and CD fragments), presumably due to the higher degree of motional freedom allowable in these protein fragments. One problem associated with the E59D whole protein variant is a prohibitively close approach of the aspartate carboxyl group to the CD calcium ion observed in the energy-minimized (pre-molecular dynamics) structure. This steric situation does not emerge during energy-minimization of the wild-type protein. The damage to the structural integrity of the calcium ion coordination site in the whole protein E59D variant is not relieved during the molecular dynamics simulation. In fact, during the course of the 300 picosecond simulation, all of the calcium ion ligands leave the primary coordination sphere. In addition, the conserved hydrogen-bonds (in the short β-sheet structure) that links the CD site to the symmetry-related EF site (in the non-mutated whole protein) is also somewhat disrupted in the E59D whole protein variant. These results suggest that the Ca2+ ion binding deficiencies in the CD loop are related, at least in part, to the unique interaction that exists between the paired CD and EF hands in the whole protein. Our theoretical results correlate well with previous studies on engineered EF-hand proteins and with all of our experimental evidence on whole silver hake parvalbumin and enzymatically-generated parvalbumin fragments.

ChemInform Abstract: The Spongistatins: Architecturally Complex Natural Products. Part 1. A Formal Synthesis of (+)‐Spongistatin 1 by Construction of an Advanced ABCD Fragment.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The Spongistatins: Architecturally Complex Natural Products—Part One: A Formal Synthesis of (+)-Spongistatin 1 by Construction of an Advanced ABCD Fragment

Zwei Fliegen mit einer Klappe: Bei der Totalsynthese des wirksamen Tumortherapeutikums (+)-Spongistatin 2 wurde die komplexe ABCD-Struktur hergestellt (siehe Bild), die auch für die Totalsynthese von (+)-Spongistatin 1 benötigt wird. In beiden Synthesen war der kritische Schritt eine säurevermittelte Epimerisierung zur Stabilisierung des axial-äquatorialen CD-Spiroketals in Gegenwart von Ca2+-Ionen.

The Spongistatins: Architecturally Complex Natural Products-Part Two: Synthesis of the C(29-51) Subunit, Fragment Assembly, and Final Elaboration to (+)-Spongistatin 2.

An advanced ABCD fragment (see picture) constructed on the way to the total synthesis of the potent antitumor agent (+)-spongistatin 2 has also been used in a formal total synthesis of (+)-spongistatin 1. In both cases the critical step was an acid-mediated epimerization in the presence of Ca2+ ions to stabilize the axial–equitorial CD spiroketal.

The Spongistatins: Architecturally Complex Natural Products-Part One: A Formal Synthesis of (+)-Spongistatin 1 by Construction of an Advanced ABCD Fragment.

An advanced ABCD fragment (see picture) constructed on the way to the total synthesis of the potent antitumor agent (+)-spongistatin 2 has also been used in a formal total synthesis of (+)-spongistatin 1. In both cases the critical step was an acid-mediated epimerization in the presence of Ca2+ ions to stabilize the axial–equitorial CD spiroketal.