On gas phase alpha-effects. 1. The gas-phase manifestation and potential SET character.

The possibility of a gas-phase alpha-effect has been explored for the methyl transfer from methyl formate to hydroxide, hydroperoxide, and ethoxide by computing barrier heights at the HF/6-311++G(2df,2p) level of theory. The alpha-nucleophile (hydroperoxide) is found to have a lower barrier than the gas-phase-acidity-matched normal nucleophile (ethoxide) by 3.6 kcal/mol, offering evidence for a gas phase alpha-effect. A Shi-Boyd analysis for these reactions indicates that there is more single-electron-transfer character in the hydroperoxide transition state than for either hydroxide or ethoxide, further bolstering the existence of a gas-phase alpha-effect and the appropriateness of the Hoz model for the alpha-effect.

The alpha-effect in methyl transfers from S-methyldibenzothiophenium fluoroborate to substituted N-methylbenzohydroxamates.

Studies of the alpha-effect show increased reactivity of nucleophiles having lone pairs of electrons on atoms neighboring the lone pair involved in reactivity when compared to the basicity of the nucleophiles. Hammett-type plots and Brönsted-type plots of substituted methylphenyl sulfates vs hydrogen peroxide anions and substituted N-methylbenzohydroxanates (NMBH) with substituted methylarenesulfonates or substituted arenedimethylsulfonium ions have large rho or beta(nuc) values, indicating a putative tightening of the usual S(N)2 transition states (anti-Hammond effect). Electrochemical studies of S(N)2-SET or reactivity indicate that SET character occurs in looser transition states, whereas S(N)2 transition states are associated with greater tightness. The alpha-effects for the series of sulfonium salts in completion reactions for 3-ClNMBH anions and 3-nitrophenolate anions are (log k(alpha)/k(normal)) 1.124 for dimethylphenyl sulfonium, 1.512 for dimethyl-1-naphthyl sulfonium, 1.835 for dimethyl-9-anthracenyl sulfonium, and 1.137 for S-methyldibenzylthiophenium. Correlations of the sizes of alpha-effects with typical SET (or ET) experimental parameters and the inverse dependence of the size of the alpha-effect on electron demand indicate inclusion of SET character in these S(N)2 transition states, vs no (or at least diminished) SET character in normal transition states. This dichotomy of tighter S(N)2 transition states, but looser SET transition states indicated in the alpha-effect, is examined in the present work.

Heteroarotinoids inhibit head and neck cancer cell lines in vitro and in vivo through both RAR and RXR retinoic acid receptors.

A class of less toxic retinoids, called heteroarotinoids, was evaluated for their molecular mechanism of growth inhibition of two head and neck squamous cell carcinoma (HNSCC) cell lines SCC-2 and SCC-38. A series of 14 heteroarotinoids were screened for growth inhibition activity in vitro. The two most active compounds, one that contained an oxygen heteroatom (6) and the other a sulfur heteroatom (16), were evaluated in a xenograph model of tumor establishment in nude mice. Five days after subcutaneous injection of 10(7) SCC-38 cells, groups of 5 nu/nu mice were gavaged daily (5 days/week for 4 weeks) with 20 mg/kg/day of all-trans-retinoic acid (t-RA, 1), 10 mg/kg/day of 6, 10 mg/kg/day of 16, or sesame oil. After a few days, the dose of t-RA (1) was decreased to 10 mg/kg/day to alleviate the side effects of eczema and bone fracture. No significant toxic effects were observed in the heteroarotinoid groups. All three retinoids caused a statistically significant reduction in tumor size as determined by the Student t-test (P < 0. 05). Complete tumor regression was noted in 3 of 5 mice treated with t-RA (1), 4 of 5 mice treated with 16, 1 of 5 mice treated with 6, and 1 of 5 mice treated with sesame oil. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to determine that the expression levels of RARalpha, RXRalpha, and RXRbeta were similar in the two cell lines, while RARbeta expression was higher in SCC-2 over SCC-38, and RARgamma expression was higher in SCC-38 over SCC-2. Receptor cotransfection assays in CV-1 cells demonstrated that 16 was a potent activator of both RAR and RXR receptors, while 6 was selective for the RXR receptors. Transient cotransfection assays in CV-1 cells using an AP-1 responsive reporter plasmid demonstrated that t-RA (1), 6, and 16 each inhibited AP-1-driven transcription in this cell line. In conclusion, the growth inhibition activity of the RXR-selective 6 and the more potent growth inhibition activity of the RAR/RXR pan-agonist 16 implicate both RARs and RXRs in the molecular mechanism of retinoid growth inhibition. Moreover, the chemoprevention activity and the lack of toxicity of heteroarotinoids demonstrate their clinical potential in head and neck cancer chemoprevention.

The alpha-Effect in Benzyl Transfers from Benzylphenylmethyl Sulfonium Salts to N-Methylbenzohydroxamate Anions.

The investigation of the occurrence of the alpha-effect in group transfers from phenyldialkyl sulfonium ions where one alkyl group is benzyl allows an assay of the effect of changing the nature of the C atom being transferred. The size of the alpha-effect responds to increasing electron demand, as methyl transfers do. Quantitative relationships between the size of the alpha-effect are established from both the nucleophilic side and the leaving group side of the S(N)2 transition state.

alpha-Effect with Substituted N-Methylbenzohydroxamates and Substituted Phenyldimethylsulfonium Salts: Toward Understanding of an Intrinsic alpha-Effect.

Increasing electron demand in the reactions of G-NMBH anions with substituted phenyldimethylsulfonium ions decreases the alpha-effect for the methyl transfers toward 1.0 (zero effect). An extrapolation shows the possibility of an inverse effect (<1.0). The reactivity of G-NMBH anions correlates with SET parameters and with the known propensity of phenyldimethylsulfonium ions to accept a single electron into a sigma C-S orbital concomitant with expulsion of a CH(3) group. These correlations indicate inclusion of some SET character into the wavefunction of the S(N)2 transition state for these reactions, in agreement with the Shaik and Pross SCD model of the S(N)2 reaction.

Quantification of the three point receptor hypothesis of Cheng and Zee-Cheng.

The placement of three heteroatoms at the corners of an acute angle triangle was found to correlate roughly with the antineoplastic activity of a wide range of compounds by Cheng & Zee-Cheng (1972, J. Pharm. Sci. 61, 485). Since then the synthetic routes to compounds having a large number of degrees of freedom, as in the 1,4-dihydroxy-5,8-bis([2-(2-hydroethyl)amino]ethyl) amino-9,10-anthracenedione (DHAQ, mitoxantrone) have been discovered. The subsequent high activity of DHAQ vs. numerous cancers has partially verified the worth of the original hypothesis. Quantitative verification of pharmacophoric hypotheses as theories necessitates the use of Popper's risky experiments. These experiences give rise to verification because, unenlightened by the theory undergoing testing, they would predict a result that would refute the theory. Computational chemistry allows such a confirmation through molecular modeling. The molecular force field, MMX, gives confirmation of the theory by showing the riskiness of the synthetic production of DHAQ for the gas phase. The MM+ forcefield in an aqueous medium computation (132 water molecules) shows that the confirmations of DHAQ does not change appreciably from the gas phase. This computation adds a considerable risk. Aquation could significantly change the favorable conformations of the very conformationally free DHAQ molecule. The fact that it does not confirm that the Zee-Cheng and Cheng hypothesis is a strong one. Additionally, a quantitative relationship arises from the new model for the N-O-O atomic placement. This new quantitative relationship further predicts quantitative risky experiments for further verification (falsification).

CH2 (+) transfer to pyridine nucleophiles: a means of producing α-distonic ions.

The distonic radical cation C5H5N(+)-(·)CH2 can be generated by the reactions of neutral pyridine with the radical cations of cyclopropane, ethylene oxide, and ketene, as well as with the [C3H6](+) ion from fragmentation of tetrahydrofuran. The distonic product ion can be distinguished from isomeric methylpyridine radical cations because the former gives characteristic [M-CH2](+), [M - CH2NCH](+), and a doubly charged ion, all of which are produced on collisional activation. Furthermore, the distonic species completely transfers CH2 (+) to more nucleophilic, substituted pyridines. These properties are all consistent with the assigned distonic structure. Another distonic isomer, the (3-methylene) pyridinium ion, can be distinguished from the (1-methylene)pyridinium ion on the basis of their different fragmentation behaviors. The latter ion exhibits higher stability (lower reactivity) than the prototypal [·CH2NH3 (+)], making available a distonic species whose bimolecular reactivity can be readily investigated.