New non-cytotoxic taxanes synthesized from 10-deacetylbaccatin III and special hydrophobic acylating agents show remarkable MDR reversal activity (⩽99.8%) against drug-resistant human breast cancer cells when co-administered with paclitaxel or doxorubicin. This activity is ascribed to the highly efficient blocking of P-glycoprotein efflux by these new taxanes.

A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III was synthesized by means of the beta-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3'- and 3'-N-positions exert marked effects on the activity. For the substituents at C-3', the cytotoxicity decreases in the order 2-furyl approximately 2-methyl-1-propenyl > or = 2-methylpropyl > (E)-1-propenyl > or = n-propyl > phenyl > > 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR.

Taxol (paclitaxel), a microtubule stabilizer with antitumor activity, mimics the actions of lipopolysaccharide (LPS) on murine macrophages (Mφ). In the present study, a variety of synthetic analogs of paclitaxel were examined for their potencies to induce nitric oxide (NO) and tumor necrosis factor (TNF) production by peritoneal Mφ from LPS-responsive C3H/HeN, and LPS-hyporesponsive C3H/HeJ mice, and by Mφ-like LPS-responsive J774.1 and its mutant LPS-hyporesponsive J7.DEF3 cells. In this structure-activity relationship study, we found that (i) the benzoyl group at the C-3′ position of paclitaxel is the most important site to activate C3H/HeN Mφ; (ii) the phenyl group at C-3′ is not a requisite for the activity; (iii) there is good correlation between NO and TNF production by the Mφ in response to compounds, except for the analogs having atert-butoxycarbonyl (10-acetyldocetaxel) or a thiophene-2-carbonyl group at C-3′-N instead of a benzoyl group, which is more dominant in TNF than in NO production; (iv) the compounds tested induce neither NO nor TNF production by C3H/HeJ Mφ; (v) active compounds to C3H/He Mφ induce TNF production by J7.DEF3 cells as well as J774.1 cells; and (vi) there is no correlation between the NO/TNF inducibility to C3H/HeN Mφ and growth inhibitory activity against Mφ-like J774.1 and J7.DEF3 cells. These data also suggest that the binding of taxoid/LPS to tubulin is not essential for the Mφ activation.

The free energies of activation at 110 K for rotation about the exocyclic C—C bonds in 2,6-difluorobenzaldehyde and 2,4,6-trifluorobenzaldehyde, in dimethyl ether solutions, are 18.8 ± 0.5 and 20.0 ± 0.5 kJ mol−1, respectively, as determined from 19F{1H} dynamic nuclear magnetic resonance measurements. For the parent compound ΔG≠ is 32.2 kJ mol−1 in the same solvent. These free energy barriers, the lowest available for benzaldehyde derivatives, are likely a result of steric and electrostatic repulsions between the C+—O− and C+—F− bonds. Computations of the spectroscopic barrier in the 2,6-difluoro compound at various levels of molecular orbital theory imply that the barrier is predominantly twofold, with a fourfold component of opposite sign, whose magnitude is about 10% of the twofold component. A correlation-gradient computation, MP2/6-31G*, finds a barrier height of 18.6 kJ mol−1 for this compound, lower by 3.0 kJ mol−1 than found with the 6-31G* basis and 2.9 kJ mol−1 with 6-31G**. Similar computations are compared for the parent compound and the 4-fluoro, 2,4,6-trifluoro, and 3,5-difluoro derivatives. Linear relationships exist between the computed spectroscopic barriers (ΔE values at absolute zero for the free molecules) and the free energy barriers for benzaldehyde and the four fluoro derivatives; the theoretical barriers utilize 6-31G** and correlation-gradient MP2/6-31G* procedures. For the 2,6-difluoro derivative, the computed frequencies of the torsional motions about the exocyclic C—C bond yield spectroscopic twofold barriers. These barriers are much lower than the computed energy differences between the planar and perpendicular conformers, perhaps because the negative fourfold components flatten the potential at its minimum. A rough estimate of the relationship between ΔG≠ and ΔE0 for the 2,6-difluorobenzaldehyde suggests that the solvent increases the internal barrier by only about 3 kJ mol−1. By way of contrast, the AM1 barriers, scaled by a factor of 1.9 (as previously recommended) range from 17.3 to 22.6 kJ mol−1, the ΔG≠ values from 18.8(5) to 34.4 kJ mol−1, and the MP2/6-31G* (correlation-gradient) barriers span 18.6 to 36.8 kJ mol−1 for benzaldehyde and the four fluorine derivatives. It seems likely that the internal barrier in benzaldehyde is considerably larger than that modeled on torsional frequencies. Keywords: Free energies of activation, internal rotational barriers in 2,6-difluoro- and 2,4,6-trifluorobenzaldehyde; molecular orbital computations, internal rotational barriers in 2,6-difluoro- and 2,4,6-trifluorobenzaldehyde; correlation gradient computations on internal barriers in benzaldehyde and four of its fluorine derivatives.

Precise 1H nuclear magnetic resonance spectral parameters are reported for salicyladehyde and its 3-fluoro and 5-fluoro derivatives in nonpolar solutions. Such data are also given for the 2-mercapto, 2-methylthio, and 2-methoxy derivatives of benzaldehyde. Comparison of the long-range coupling constants in the various compounds and their conformers shows a large perturbation of their magnitudes by hydrogen bond formation. For the salicylaldehyde system, the perturbation is particularly large for couplings involving the aldehyde proton and protons or fluorine nuclei placed ortho to the hydroxyl group. For example, 5Jt (F, CHO) is reduced by about 50%. The perturbation, as expected, is much smaller for coupling constants of nuclei remote from the site of the hydrogen bond. In 2-mercaptobenzaldehyde the long-range coupling constants are also sensitive to hydrogen bond formation, those involving the sulfhydryl proton markedly so compared to the hydroxyl proton in salicylaldehyde. The strength of the [Formula: see text] bond is discussed. It is argued that the reference conformer for the mercapto compound in such a discussion is less easily defined than for salicylaldehyde because [Formula: see text] are similar to [Formula: see text] energies. The experimental data for the CCl4 solutions imply a free energy of formation of the [Formula: see text] bond of 4.8(5) kJ/mol at 300 K. Molecular orbital computations on the four planar conformers of each salicylaldehyde and 2-mercaptobenzaldehyde with the 6-31 G**(5D) basis are reported. For salicylaldehyde, the [Formula: see text] arrangement is taken as the reference conformer, with a computed energy of 25.7 kJ/mol relative to the hydrogen-bonded structure. For 2-mercaptobenzaldehyde, the [Formula: see text] and [Formula: see text] conformers are calculated to be isoenergetic, at 5.1 kJ/mol relative to the hydrogen-bonded conformer. Hence either arrangement serves as a reference structure in computations of the strength of the hydrogen bond. The computations are consistent with the experimental results for solutions of the molecules under discussion. An appendix gives the computed geometries of the eight planar conformers, as well as some atomic charges, allowing a rationalization of the relative energies of the conformers.

Precise 1H and 19F nuclear magnetic resonance chemical shifts and spin–spin coupling constants are reported for 4 mol% solutions of 2-fluorobenzaldehyde (2FB) and 3-fluorobenzaldehyde (3FB) in CS2/C6D12/TMS/C6F6 and acetone-d6/TMS/C6F6 solvent mixtures at 300 K. A small amount of the O-cis conformer of 2FB is present even in the nonpolar solvent mixture, corresponding to a free energy difference of 7.6(3) kJ/mol between the planar O-cis and O-trans conformers. In the polar solvent, this number decreases to 4.5(2) kJ/mol. The O-cis and O-trans conformers of 3FB have very similar abundances in the two solvent mixtures, the former being favored by a free energy difference of 0.38(4) kJ/mol in the nonpolar medium and, unexpectedly, considering its highly polar nature, by only 0.27(4) kJ/mol in the polar environment. STO-3G MO computations, with geometry optimization, of the internal rotational potentials of 2FB and3FB confirm the planarity of the O-cis conformer of 2FB, that is, that the planar form is more stable than a somewhat twisted conformer. 6-31G MO calculations for the four planar conformers yield structures of potential use in the fitting of rotational spectra in the vapor. Extrapolation of the 1H nmr data for 2FB implies a free energy difference of 11.5 ± 0.6 kJ/mol at 300 K in the vapour favoring the O-trans form, midway between the two theoretical estimates. The present experiments and computations are compared with the latest rotational, vibrational, and electronic spectra and with other assessments of the relative conformer stabilities in the vapor and in solution. Keywords: NMR for 2- and 3-fluorobenzaldehyde; conformations in solution and vapor, for 2- and 3-fluorobenzaldehyde; MO calculations, 2- and 3-fluorobenzaldehyde.

ChemInformVolume 21, Issue 5 Physical Organic Chemistry ChemInform Abstract: An NMR Study of Steric and Hyperconjugative Barriers in Benzyl X(CH3)3, X: C, Si, Ge, Sn, Pb. T. SCHAEFER, T. SCHAEFER Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this authorG. H. PENNER, G. H. PENNER Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this authorC. S. TAKEUCHI, C. S. TAKEUCHI Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this authorC. BEAULIEU, C. BEAULIEU Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this author T. SCHAEFER, T. SCHAEFER Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this authorG. H. PENNER, G. H. PENNER Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this authorC. S. TAKEUCHI, C. S. TAKEUCHI Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this authorC. BEAULIEU, C. BEAULIEU Dep. Chem., Univ. Manitoba, Winnipeg, Manitoba R3T 2N2Search for more papers by this author First published: January 30, 1990 https://doi.org/10.1002/chin.199005045AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume21, Issue5January 30, 1990 RelatedInformation

The 1H nuclear magnetic resonance spectra and their analyses are reported for benzyltrimethyl X (X = C, Si, Ge, Sn, Pb) and for the 2,6-dichloro derivatives where X = Si, Ge, Sn, Pb. The steric barrier to rotation about the Csp2—Csp3bond for X = C, based on the long-range proton–proton coupling constant over six bonds, 6J(H,CH2), must be greater than 20 kJ/mol. Unexpectedly, 6J(H,CH2) implies that the barriers for X = Si, Ge, Sn, Pb have relatively minor steric components. If these barriers are dominated by hyperconjugative interactions of the C—X bond with the aromatic π system, then they are probably mainly twofold in nature. Furthermore, their magnitude is likely to be near 9.5 kJ/mol for X = Si, Ge, Sn and may be as high as 12 kJ/mol for X = Pb. Keywords: NMR, benzyl X(CH3)3, X = C, Si, Ge, Sn, Pb; NMR, conformations; NMR, hyperconjugation.

6J(H,CHO), the long-range coupling constant between the aldehydic and para protons in benzaldehyde, has not been detected, possibly because the σ–π interaction giving rise to a negative coupling is intrinsically rather small and because the internal barrier to rotation about the [Formula: see text] bond is large. However, 6J(H,CHO) in some meta substituted derivatives is actually positive and as large as 0.09 Hz in 3,5-difluorobenzaldehyde; the barrier to internal rotation in this molecule is some 4 kJ/mol lower than in the parent molecule. The magnitude of 6J(H,CHO) in these derivatives correlates well with σR.ST values, a recent set of substituent constants derived from 13C nuclear magnetic resonance chemical shifts of the β carbon in styrene derivatives. It is hypothesized that the substituents with negative σR.ST values stabilize an ionic valence bond structure that has a positive 6J(H,CHO). A brief discussion of 4J(H,CHO) in some of these molecules is also presented. Keywords: NMR, spin coupling NMR, benzaldehyde.

The CNDO/2 and INDO MO FPT values for 5Jm(F,CH3) in 3-fluoro- and 3,5-difluorotoluene are exactly reproduced by A cos2 θ + B sin2 θ + C sin2 (θ/2). Here θ is the angle by which the α C—H bond twists out of the benzene plane. Adjustment of A,B, and C to give an agreement with experiment for 3,5-difluorotoluene yields an equation, best considered empirical, which is tested by 5J(F,CH) in 3,5-difluoroethylbenzene and 3,5-difluoroisopropylbenzene. The equation reproduces 5J(F,CH) in these two compounds, the values of [Formula: see text] being derived from 6Jp(H,CH), the spin–spin coupling constants over six bonds between the α and para ring protons. 5J(F,CH) is obtained for the asymmetrical compounds, 2,3-difluorobenzylidene diacetate and 2-bromo-5-fluorobenzylidene diacetate. It is shown how 5J(F,CH) in the latter can discriminate between two conformers, each of which, on the basis of 6J(H,CH), will be characterized by a large degree of torsion about the [Formula: see text] bond.

The 13C nuclear magnetic resonance chemical shifts and the 13C,19F spin–spin coupling constants are reported for 4,4′-difluorophenyl ether and 4-fluorophenyl phenyl ether in CS2 and in acetone-d6 solutions. An estimate of 6J90, the extremum in the σ–π coupling constant between the 19F nucleus on one ring and the ipso13C nucleus on the other, is obtained from measurements on 2,6-dibromo-4-fluorophenyl phenyl ether. The ensuing estimates of [Formula: see text], the expectation values of sin2 θ as obtained from 6J(13C,19F), are compared with those obtained from STO-3G MO computations for diphenyl ether and its 4-fluoro derivatives. These computations give conformational energies at 30° intervals of the angles of twist about the two C—O bonds. In rough agreement with C-INDO computations, interconversion of the helical forms is calculated to occur most easily by the so-called one-ring flip mechanism; the barrier to interconversion is less than 1 kJ/mol in the ether and its 4-fluoro derivatives. It appears that the conformational behaviour of these derivatives is unaltered by passage from CS2 to acetone solutions at 300 K. Furthermore, [Formula: see text] values from 6J(13C,I9F) in solution are very similar to those obtained from the computations on the free molecules. If this agreement is not accidental, then it may arise from a high degree of flexibility of the molecules in which, by a disrotatory or one-ring flip mechanism requiring a very low energy of activation, one helical or C2 conformation can be converted to another. The other conformations have considerably higher energies and the solvents do not appear to lower these energies enough to favor their populations significantly at 300 K.

The 1H nmr spectra of the benzene-1,2- and -1,3-dicarbaldehydes in carbon tetrachloride, benzene-d6, and acetone-d6 solutions at 300 K are analyzed. The stereospecific long-range couplings over five formal bonds between the sidechain and ring protons show that the 1,2 isomer exists as an 87:13 mixture of the cis–trans and trans–trans conformers in carbon tetrachloride. These populations are insensitive to solvent. Molecular orbital calculations utilizing extensive geometry optimization procedures imply that the cis–cis form, with proximate C=O bonds, is indeed of negligible significance as assumed in obtaining the populations of the other forms. Further calculations define a pathway of relatively low energy for interconversion of the two abundant forms, in agreement with dynamic nmr studies. For the 1,3 isomer the long-range couplings provide a check of the conformer populations deduced from dipole moment and 13C nmr studies. For example, if the cis–trans form is 70% abundant, as deduced from the dipole moment in benzene solution, then the long-range couplings imply that the population of the cis–cis conformer is insignificant.