Small-Molecule Analogs

There are many examples of current efforts where small organometallic compounds are being investigated for biomedical application. Following is a short description of some of these. 

The main function of tamoxifen is to block or interfere with the action of estradiol, one of a group of female hormones known as esterogens. Tamoxifen metabolizes forming hydroxytamoxifen that binds to an estrogen receptor preventing the cell from growing and dividing. 

In a similar study, ferrocene-substituted tamoxifens, ferrocifens, exhibited good antiproliferative effects on several breast cancer cell hnes. These ferrocifens are the first drugs that show good activity against both the hormone-dependent and hormone-independent breast cancer cells. 

The hydroxyl derivative, hydroxyferrocifen, shown below, also inhibits cell growth in kidney cancer and ovarian cancer cell lines. Live animal tests in rats and mice show that some of the hydroferrocifen derivatives are less toxic than tamoxifen itself 

This group also synthesized and studied a series of Ru, W, and Co complexes of 17-estradiol. ° These modified hormones showed good affinity for the binding at the estrogen receptor site. One of these compounds is illustrated below. 

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Another important class of electron-transporting emitter is the distyryl-arylenes. These have been explored most extensively by workers at Idemitsu Kosan [31, 32], with the bulk of the published data focusing on a compound designated as DPVBi (see Table 13-2). This class of materials may be considered as small molecule analogs of the PPV polymers, with distyrylbenzene and its derivatives ]33] as prototypical examples. Because of the short conjugation length they tend to be blue emitters. 

Characterization of structural, spectroscopic, and reactivity properties of model compounds—that is, metal cofactor small molecule analogs. 

In the case of iron-containing small molecule analogs of Mb and Hb a much rockier road to successful model compounds was encountered. Even though the syntheses of iron porphyrin complexes were carried out in analogous manner to the cobalt species described above, their irreversible oxidation to the p-oxo dimer upon... 

Kinetic and mechanistic studies of the reactivity Zn-Oh ( = 1 or 2) species in small molecule analogs of zinc-containing metalloenzymes, 41, 81 Kinetics and spectroscopy of substituted phenylnitrenes, 36, 255 Kinetics, of organic reactions in water and aqueous mixtures, 14, 203 Kinetics, reaction, polarography and, 5, 1... 

As in the case of LCP/conventional polymer blending, little data exists on the blending of LCPs of different inherent chain architecture or mesophase symmetry. Publications from the laboratories of Ringsdorf [80] and Finkelmann [81] show phase separation in blends of sidechain nematics with other similar polymers or small molecule analogs. It is now established that, in contrast to the behavior of low molecular weight LCs, LCPs are often immiscible. 

Kinetic and mechanistic studies of the reactivity Zn-Ohn (n = 1 or 2) species in small molecule analogs of zinc-containing metalloenzymes, 41, 81... 

Significant efforts are currently focused on developing novel agents for multiple myeloma. These include CC5013, a small molecule analog of thalidomide with immunomodulatory effects the proteasome inhibitor PS341 and arsenic trioxide. 

Many oxidative addition complexes are stable because four and higher coordination inhibits decomposition via de-insertion and elimination. For benzylhalides that are pendant to a polymer main chain, compounds that exhibit T 3-bonding to the benzyl group are possible. The small molecule analog is the T 3-benzylpalladium chloride dimer. This complex is neither electronically nor coordinately saturated and is therefore not inert to ligand addition. 

It is also possible that stretched (high pH) versus coiled (low pH) polymer chains may exhibit different photophysics. This was commented by Chou and Jellinek in their early report on PMAA photochemistry, and a detailed TREPR study of pH-dependent cage effect manipulation using initiator-labeled PMAA was reported by Maliakal et al. " It has been reported by Mittal and coworkers that for small molecule analogs of PAA and PMAA, the quantum yield for Norrish I cleavage drops to zero for the completely deprotonated structure. For PMAA, we also observe a pH dependence in the TREPR signal intensities (data not shown). The data in Fig. 14.7 are the hrst experimental evidence for such an effect in PAA radicals. 

Kabanov and cowodkers conducted extensive studies on tiie scdvolysis of jdienyl esters catalyzed by partially alkylated pdyvinylpyiidines I. These polymers reportedly exhfliited exceptionally high activity in the hydrolytis of ph i esters, as compared with small-molecule analogs. Unfortunately, however, Kabanov stated recent-... 

The c ytic effect of some triazoles 5 and poly-3-vinyl-l, 4-triazole 6 was invest ated in the solvolyses of neutral, negatively and positively charged phenyl esters (92). For aU systems, the catalytic effect exhibited a linear dependence on the concentratitm of the respective anionic forms. The polymer possessed a lessened reactivity compared with a small-molecule analog. 

The polymer was 10 times as effective as a small-molecule analog, dimethy-benzylamine 10 in the case of p-nitrophenyl caproate 6. The rate enhancement is larply attributed to favorable binding. No difference in catalytic activity was found between linear and branched polyethyleneimine derivatives. It is curious that desorption of the product is rate-limiting according to the kinetic analysis. 

Aqueous solutions of poly(ethylene oxide), (-CH20CH2-)m (PEO) exhibit unusual phase behavior in the sense that the polymer is soluble in water at room temperature, but phase separates at higher temperatures. Molecular interpretations of this unusual behavior implicate the effect of hydration on the conformational equilibria of the polymer chains based on studies of conforma-honal equilibria of small-molecule analogs of PEO e.g., 1,2 dimethoxyethane (DME), CH3OCH2CH2OCH3. Note that DME conformations are characterized by three consecutive dihedral angles centered on the 0-C, C-C, and C-0 bonds along the chain backbone, which can be found in the trans t, 180°),... 

In a natural product-based DOS library of small molecules, analogs of dysiherabine (Figure 9.7a), a natural... 

There is extensive evidence from site-directed mutagenesis and other studies of enzymes that catalyze proton transfer that acidic and basic amino side chains and, in some cases, metal cations, are required for the observation of efficient catalysis. However, catalysis of the deprotonation of a-carbonyl by small molecule analogs of these side chains, and by metal cations is generally weak. Relatively little attention has been directed towards understanding the mechanism for the enhancement of Bronsted acid/base and electrophilic catalysis for enzyme-catalyzed reactions... 

The polyacrylophenones represent another important category of photosensitive polymers. Substitution on the phenyl ring can alter both the efficiency and mechanistic pathway to reaction products (38). Early work (39) showed that the photochemistry could be related to that of small-molecule analogs. Work at the Slovak Academy of Sciences (40) has extended to a very large number of substituted derivatives. In common with other ketone systems, the quantum yields for chain scision are reduced significantly in the solid phase. Some of this is due to the restrictions on molecular mobility, which reduce the quantum yields of type-II photoprocesses. Another important factor is the extensive triplet migration, which, in the solid phase, leads to quenching by reaction products (41), such as the olefin produced by the type-II photoprocess. 

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