Hybrid NORMs

NO-NSAIDs were conceived as prodrugs to utilize NO release for side effect attenuation. However, growing evidence for the chemotherapeutic and chemo-preventive attributes of NO release has led researchers to attempt to harness these properties. The NO releaser in these hybrid NORMs is, in the parlance of chemotherapeutics, a drug warhead. Hybrid NORMs have come to dominate the field therefore, before reviewing the individual classes of NORMs, it is important to examine the concept of the hybrid NORM. 

Six classes of hybrid NORMs are depicted in (Fig. 20.2), incorporating three classes of NO-releasing warheads NONOate, nitrate, and furoxan. Despite the very different chemistry of NO release from these three warheads, and the diverse stmc-tures of the hybrid NORMs, there are many common featnres. All five hybrids presented (A-C, E, F) contain a salicylate NSAID as the bioactive carrier. In four of these (A-C, F) a labile linker connects to the warhead, liberating the bioactive carrier by esterase bioactivation. In the fifth ( ) the labile linker is a disulfide that can be bioactivated by thiol-disulfide exchange. 

Molecular deconstruction of the hybrid NORMs, GT-094, NCX-4040, and NCX-4016 (Dunlap et al. 2007, 2008 Hulsman et al. 2007), demonstrated that the chemopreventive and chemotherapeutic properties were reproduced in appropriate control compounds that did not possess an NO-release warhead. Similarly, the biological activity of JS-K has been proposed to result in part from NO-independent actions of the carrier (Ren et al. 2003). In all these cases of NO-independent activity, the hybrid NORMs have a common feamre, the provision of a thiophilic electrophile... 

Fig. 20.2 Six representative hybrid NORMs eontaining furoxan, nitrate, and NONOate warheads. Eaeh molecule incorporates at least two eomponent parts a bioactive carrier and a warhead. All examples shown have labile linkers that are bioactivated to release bioaetive molecules ineluding the warhead. In most eases the warhead requires further bioactivation to release NO bioaetivity. The figure illustrates the uniform dependence on reactions with biological thiols and products that will contribute to varied levels of cellular oxidative stress...

The prospects and obstacles for hybrid NORMs in cancer treatment may be summarized thus ... 

Hybrid NORMs require one or more bioactivation process which may be utilized to enhance selectivity for cells and tissues multiplicity of bioactivation processes and the diffusibility of NO are not compatible with specificity. 

The majority of hybrid NORMs provides NO bioactivity without acting as pure NO donors the exception being the NONOates, which are true NO donors. NO release is rarely measured for NORMs the common use of surrogates (N02, oxyHb metHb) has often produced confusion in the field and is not compatible with the drive toward agents that release specific nitrogen oxides, such as NO itself or nitroxyl (NO) (King 2005 Miranda et al. 2005). 

Hybrid NORMs are expected to induce cellular oxidative stress by release of NOjc, thiophiUc electrophiles, and through depletion of bioactivating species. High levels of oxidative stress and NO release are compatible with induction of apoptosis, DNA damage, and a role in chemotherapy, while lower levels of oxidative stress and lower rates of NO release are commensurate with induction of multiple chemopreventive pathways. 

The importance of bioactivation for all hybrid NORMs requires care in extrapolating results obtained in vitro (where bioactivation may be at very low levels) to predict properties in vivo. For example, despite the demonstrated in vitro impotence of the warheads of GT-094 and NO-ASA, the GI protective effects of the nitrate warheads will be important in vivo. 

The comparison of a hybrid NORM drug versus a comparable combination therapy has rarely been studied in vivo for example, a cocktail of NSAID + ISDN (isosorbide dinitrate) compared to an NO-NSAID. In one case where a comparison was made with NCX 4016 the cocktail was equi-efficacious (Brzozowska et al. 2004). In several hybrid NORM designs, such as JS-K and GT-094, bioactivation to release the warhead bioactivity is contingent upon the presence of the linker (Shami et al. 2003 Zavorin et al. 2001). 

The NO-ASA family of NO-NSAIDs, notably NCX 4016 [Fig. 20.2(a)] and NCX 4040 [Fig. 20.2(b)], has been extensively researched. These two isomeric hybrid NORMS differ only in the snbstitution of the linker group. Hulsman et al. was the first to comment that in NCX-4040 the presnmed invisible linker is in fact solely responsible for the anti-tumor effect of the molecule and that both the NO-release warhead and the ASA are passive bystanders (Hulsman, Medema et al. 2007). The Unker warhead moiety is efficiently bioactivated to a quinone methide thiophiUc electrophile, in simile with much earUer literature reports (Myers and Widlanski 1993). Molecules in which the nitrate group of NO-ASA was replaced by a comparably good leaving group (termed X-ASA Fig. 20.12) showed very similar properties in vitro with respect to activity (1) cytotoxic/genotoxic (2) antiproliferative (3) chemopreventive (ARE activation - phase 11 enzyme induction) and (4) the anti-inflammatory (Dunlap et al. 2(X)7, 2008). 

Fig. 20.12 Comparison of hybrid NORMs and X-ASA molecules the nucleofugality and isomeric location determines the formation of the reactive quinone methide, a thiophilic electrophile...

Fig. 15.8 Example problem illustrating the iteration path for the hybrid Newton and time-integration approach (solid lines) and the time-marching approach alone (dashed line). The contours are for the maximum norm of residuals of the steady-state equations.

Regarding disciplinary sources, hybrid nanomaterials are more diverse than the norm in the chemistry disciplines in which it is embedded. As shown in Figure 24.3, it draws mainly on disciplines from chemistry (organic, inorganic, physical) and materials science (multidisciplinary materials science, nanotechnology, condensed matter, applied physics), as well as from certain areas of biology (biophysics, biotechnology, biochemistry), which provide either biomimetic ideas or arenas of application. 

Currently, most base stations are grid tied with the electricity grid providing prime power. Backup comes in the form of diesel generators, and to a much lesser extent some form of renewable - battery hybrid system. Off-grid base stations are much less common but when they are installed the norm is a two-diesel generator system, where one acts as the primary with the backup power provided by the other. 

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