Topo inhibition

If a strip of cells is removed from a confluent monolayer of untransformed cells (e.g. 3T3 mouse embryo cells) then the cells at the edge of the wound are stimulated to synthesise DNA and divide. They quickly colonise the unoccupied area of the wound. This phenomenon known as topo inhibition (Dulbecco, 1970) is now explained by the presence in cells on the edge of the wound of an increased surface area exposed to the medium (i.e. neighbouring cells have been removed) (Stoker, 1973 Dulbecco and Elkington, 1973). 

Topo II inhibition remains the most per suasive mechanism to explain the antitumor activity of anthracyclines accordingly, limited clinical studies showed that tumor... 

Hoechst 33342 [2 -(4-ethoxyphenyl)-5-(4-methyl-l-piperazinyl)-2,5 -bi-IH-benzimidazole Ho342 I], a bisbenzimidazole dye, binds to adenine/thymine-rich regions in the minor groove of DNA. This dye induces apoptosis and inhibits topo 1 activity in vivo. It has been suggested that the destruction of immunoreactive topo I and topo I-DNA complexes or cleavable complexes results in inhibition of topo I activity, a key step in the Hoechst 33342-induced apoptotic process [40]. 

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Wall et al. [46] synthesized a series of X-camptothecin analogues (IV where, X = 9- or 10- or 9,10- or 10, 11- or 9,10,11- substitutions) and evaluated their inhibitory activity against DNA topo 1. Using topo 1 inhibition data of these X-camptothecin analogues (IV), Eq. 2 was derived [47] ... 

In an effort to improve the water solubility of camptothecin, Rahier et al. [50] synthesized four 20-O-phosphate derivatives (VI). These compounds are freely water-soluble, stable to physiological pH, and stabilize the human topo I-DNA covalent binary complex with the same sequence-selectivity as camptothecin itself All four compounds inhibited the growth... 

Inhibition of DNA topo I activity in HCT 116 (human colon carcinoma) cells by CPT, CPT-11, SN-38, TPT, and EGCG (Table 8) ... 

The above three equations (Eqs. 10-12) for the different cell lines are very similar to each other, which suggests that the inhibition against DNA topo I is probably one of the most important antitumor mechanisms for these compounds (CPT, CPT-11, SN-38, TPT, and EGCG) against the three human colon carcinoma (HCT 116, VACO 241, and SW 480) cell lines. In these equations, the number of data points (four or five) is small, but the correlations are statistically significant. 

The inhibitory activity (% inhibition) of benzonaphthofurandiones (XIV) was evaluated by Rhee et al. [63] against topo II using a decatenation assay. From their data, Eq. 15 was developed (Table 11) ... 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

The epipodophyllotoxins, etopo-side and teniposide, interact with topo-isomerase 11, which functions to split, transpose, and reseal DNA strands (p. 274) these agents cause strand breakage by inhibiting resealing. 

Shermilamines B (37) and C (38) (and also diplamine 46) showed dose-dependent inhibition of proliferation in HCT cells in vitro and inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner [41]. These results suggest a possible cytotoxicity mechanism for these compounds. Furthermore, shermilamine B also displayed cytotoxicity against KB cells [43] and was reported as a potent regulator of cellular growth and differentiation, affecting cAMP-mediated processes [44]. 

Gemifloxacin is a third generation, oral broad-spectrum, fluorinated quinolone antibacterial agent. It acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TOPO TV), which are essential for cellular replication and bacterial growth [7]. It is... 

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