Propargylic Sulfones Research Articles

General stereoselective synthesis of ( E)- exo-alkylidene tetrahydrofurans via base-mediated cyclization of hydroxyl propargylic sulfones

The base-promoted cyclization of a number of phenyl propargylic sulfones possessing a β-hydroxyl group afforded 5-substituted ( E)-2-[(benzenesulfonyl)methylene]tetrahydrofurans 3 in >80% yield. The phenyl allenic sulfone, formed by isomerization of the phenyl propargylic sulfone under the basic conditions, is attacked by the internal alkoxide to give an allylic anion which undergoes protonation to form the conjugated exo double bond.

Remarkable tethering effect on DNA cleavage of propargylic sulfone conjugates with intercalating moieties.

A number of novel propargylic sulfone conjugates 3 and 4 with intercalating moieties were synthesized and evaluated for DNA cleavage activity through nucleic base alkylation. A remarkable enhancement in DNA cleaving potency was observed with those conjugates 3 possessing a suitable spacer, a right attachment point at the aromatic ring, and a good intercalator.

Lexitropsin Conjugates: Action on DNA Targets

Lexitropsins have been combined with epipodophyllotoxin, aromatic and aliphatic phosphonated and sulfonated compounds, bithiazoles, oligodeoxy-ribonucleotides, pyridine, imidazole, decazadecabutylamine, acridines, anthraquinones, pyrene, ellipticine, oxazolopyridocarbazole, porphyrin, nitrosoureas, benzoyl mustards, nitrogen mustards, CC-1065, psoralens, bleomycin, flavins, metal chelating moieties, enediynes, and propargyl sulfones to give the corresponding lexitropsin conjugates. In most of the cases each of the individual components of the lexitropsin conjugate retain their modes of action as far as interaction with DNA is concerned. In some cases the components of the lexitropsin conjugates altered their mode of interaction towards DNA or developed new properties. Alkyl alkanesulfonate esters are major groove alkylators. After formation of lexitropsin conjugates they become minor groove alkylators. A-T specific netropsin and distamycin accept G-C sites after forming conjugates with pyridine. CI-ENU breaks DNA after alkylation at N7 of guanine whereas its lexitropsin conjugate cleaves at A and T residues associated with affinity binding sites. Benzoyl mustard changes from a major groove alkylator (N7 of guanine) to a minor groove alkylator (adenine) after formation of lexitropsin conjugates. Epipodophyllotoxin conjugates with lexitropsins have additional sites available for topoisomerase II cleavage compared with the unconjugated agent. Thermal stability of oligodeoxynucleotides is increased after formation of a lexitropsin conjugate. In the case of lexitropsin acridine conjugates the binding of one component is compatible with DNA binding of the other component. The A-T specificity of a netropsin-oxazolopyridocarbozole conjugate is much less as compared to netropsin. Lexitropsin-psoralen conjugates bind more tightly at A-T sites of DNA compared with the individual components. The relative rate of DNA cleavage is increased with increase in the number of N-methylpyrrole units in lexitropsin-bleomycin conjugates. Phosphonated-sulfonated lexitropsin conjugates are highly active against HIV and may prove valuable for the treatment of AIDS. The benzoyl mustard-lexitropsin conjugate, i.e., FCE-24517, shows broad spectrum anticancer activity and is undergoing clinical evaluation.

Tandem Enyne Allene-Radical Cyclization: Low-Temperature Approaches to Benz[e]indene and Indene Compounds.

In an effort to lower the temperatures required to prepare multicyclic compounds using the tandem enediyne-radical cyclization, we have developed the tandem enyne allene-radical cyclization which proceeds at temperatures as low as 37 degrees C. The reactions were carried out using three different methods for the preparation of the enyne allenes. The first method involved the [3,3] sigmatropic rearrangement of an enediyne followed by a tandem enyne allene-radical cyclization. This reaction could be effected either by thermolysis (150 degrees C) or by AgBF(4) rearrangement followed by heating at 75 degrees C. A second technique utilized a [2,3] sigmatropic shift of an enediyne at -78 degrees C followed by tandem cyclization at 37 or 75 degrees C depending on the substrate. The final method involved the base-catalyzed isomerization of propargyl sulfones which yielded enyne allenes that underwent cyclization at 37 degrees C. These three sequences provide a method for the synthesis of ring systems using conditions that may be compatible with the sensitive functionality needed during the synthesis of complex natural products.

DNA cleavage of novel propargylic sulfones. Enhancement of potency via intercalating interaction

A number of novel hydroxy propargylic sulfones 7–15 were synthesized as DNA cleaving agents. Enhancement of DNA cleavage potency was observed with those compounds which could interact with DNA through intercalation of the extended aromatic rings.

The synthesis and reactivity of 3β-(2-alkynylsulfonyl)- and 3β-(2-alkynylsulfonylmethyl) androst-5-en-17-ones as inhibitors of glucose-6-phosphate dehydrogenase

3β-(Hexadec-2-ynylsulfonyl)androst-5-en-17-one, 2c, was designed as an analog of dehydroepiandrosterone sulfatide 1c, a potent, natural inhibitor of glucose-6-phosphate dehydrogenase (G6PDH). Nucleophilic substitution of 1-bromo hexadec-2-yne 11 with 3β-mercaptoandrost-5-en-17-one followed by oxidation afforded 2c. The propargylic sulfone 2c may tautomerize to the electrophilic allenic sulfone 3a and thus function as a masked affinity label of the steroidal binding site of G6PDH. Since 2c demonstrated low potency as an inhibitor of G6PDH, a sulfonylmethyl analog 4b was also designed and synthesized. Synthesis of 4b began by methylenation of androst-5-en-3,17-dione 17-ketal 6 with the Tebbe reagent, to yield the 3-methyleneandrost-5-ene 7. Hydroboration, followed by oxidation, gave a mixture of 3α- and 3β-hydroxymethyl isomers 8a and 8b, respectively. The 3β alcohol 8b was converted to the thiol 10. Alkylation of 10 with 1-bromo-2-hexadecyne 11, followed by selective oxidation, gave the desired acetylenic sulfone 4b. Insertion of the methylene in 4a and 4b significantly increased their G6PDH inhibitory properties over the initial compounds, 2b and 2c.

Synthesis, Reaction, and Cytotoxicity of Novel Propargylic Sulfones

Synthesis, Reaction, and Cytotoxicity of Novel Propargylic Sulfones

Synthesis, reaction, and cytotoxicity of novel propargylic sulfones

Abstract Propargylic sulfones 1 and 2 have been synthesized for their potent interactions with DNA. The crown ether conjugate 8 was also prepared from 1 under carefully established reaction conditions. The synthesized propargylic sulfones 2, 5, and 8 exhibited high reactivity toward sulfur-, nitrogen-, and oxygen-containing nucleophiles. Compound 1 showed an IC50 of 5.3×10−6 M against KB/P cancer cells comparable with that of the clinically used agent 5-FU.

Hybrid molecules containing propargylic sulfones and DNA minor groove-binding lexitropsins: synthesis, sequence specificity of reaction with DNA and biological evaluation.

A series of hybrids, 4-13, incorporating propargylic sulfones and minor groove-binding oligopeptide carriers, was synthesized. The anticipated preferential binding at adenine sites within the minor groove was confirmed by sequencing determination of these agents on high-resolution gels, indicating preferential alkylation at guanine, and significantly, high selectivity for 5'-GACG and 5'-GGTG. The ability of these hybrids to cleave DNA, as determined by agarose-gel assay, is consistent with the ethidium bromide fluorescence assay. The cytotoxicities of these compounds were also determined against human KB cells in vitro. Higher cytotoxic activities were observed for the compounds containing fewer N-methylpyrrole units, an imidazole group and a 2,3-disubstituted naphthyl moiety.

Synthesis and DNA cleaving properties of hybrid molecules containing propargylic sulfones and minor groove binding lexitropsins

A series of hybrids incorporating propargylic sulfones and minor groove bindin goligopeptide carriers 2-11 were synthesized and their abilities to cleave DNAd have been demonstrated.

ChemInform Abstract: Sulfone-Mediated Rupe and Raphael Rearrangements.

Abstract Base-catalysed addition of methanol to propargylic sulfones selectively gave β-ketosulfones whereas mercuric salts catalysed additions gave γ-ketosulfones. The latter process has been used to prepare one half of pyrenophorine.

Sulfone mediated Rupe and Raphael rearrangements

Base-catalysed addition of methanol to propargylic sulfones selectively gave β-ketosulfones whereas mercuric salts catalysed additions gave γ-ketosulfones. The latter process has been used to prepare one half of pyrenophorine.

Approaches Towards the Synthesis of Allenyl Azides

AbstractMethods which are known to produce allenes under mild conditions have failed to synthesize the yet unknown title compounds. These are (i) azide substitution of propargyl sulfonates, (ii) reactions of α‐azido acid chlorides with ynamines, and (iii) Wittig condensation of α‐azido acid chlorides with phosphorus ylides. The reaction products obtained are respectively azidoalkyl‐1, 2, 3‐triazoles (4), pyrrolinones (6) or pyridines (8), and a disubstituted ylide (11) or the fused triazole 12.