LOS ESCENARIOS DONDE TRANSCURRE LA ACCIÓN 3D Y

Since the discovery of cis-Pt, Pt drugs have been used in the clinic for the

treatment of a wide range of solid tumors. However, intrinsic and acquired resistance

against approved Pt compounds remain a major obstacle for their effectiveness in

cancer treatment. Therefore, extensive research has been employed in developing new

Pt analogs that may circumvent such resistance and improve therapeutic outcome of

patients. In order to achieve this goal, it is essential to take a close look at the basic

structure of Pt compounds. Pt compounds have a square planar configuration with a

general chemical structure of [Pt(X)2(L)2], in which X is an equatorial leaving (labile)

group, L is an equatorial (stable) carrier amine ligand and the central metal atom is in a

bivalent Pt (II) oxidation state [15]. Thus, cis-Pt is a simple structure with L= NH3 and X=

Cl [131]. There are some modifications that can be performed, individually or as a

group, for the synthesis of new promising Pt compounds: 1) substitution of X, L or both

with alternate chemical groups, 2) creation of different Pt isomers (cis vs. trans) and 3)

increasing the oxidation state of the Pt atom to tetravalent Pt(IV) [132]. A more detailed

explanation of each group with their respective examples will be provided in the

following paragraphs.

1) Substitution of X, L or both with alternate chemical groups:

Oxaliplatin (oxali-Pt), a third generation Pt derivative, is an excellent example

where modifications to the basic structure of cis-Pt yields a different activity profile. The

chemical structure of oxali-Pt has L= bidentate 1,2-diaminocyclohexane (DACH) and X=

35

Section 1.2.2), oxali-Pt DNA damage reflects different distortion angle and degree of

local unwinding in the formation of DNA-adducts due to its different carrier ligand.

DACH-Pt-DNA adducts formed by oxali-Pt are bulkier, more hydrophobic, more

effective at inhibiting DNA synthesis and more cytotoxic than cis-diammine-Pt-DNA

adducts formed by cis-Pt. Moreover, due to differences in unwinding and bending

angles of DNA between cis-Pt and oxali-Pt-DNA adducts, the specialized proteins

recognizing these drug-specific adducts are different. For instance, it has been shown

that the DNA damage induced by oxali-Pt is not recognized by HMGB and MMR

proteins, whereas cis-Pt adduct recognition is highly dependent on these proteins.

Thus, loss of these proteins result in resistance to cis-Pt but not to oxali-Pt [133]. As a

consequence, DNA adducts formed by cis-Pt and oxali-Pt induce the activation of

independent DNA damage signaling pathways, but which converge on p53-dependent

apoptosis.

In 2002, oxali-Pt, was approved by the FDA in the United States for the treatment

of advanced colorectal cancer, a disease in which cis-Pt treatment has proven to be

ineffective. In advanced ovarian cancer, oxali-Pt entered Phase II and Phase III clinical

trials in patients that do not respond to the current first-line treatment [133]. Clinical

results from these trials have shown synergistic effect of oxali-Pt cytotoxicity in

combination with other chemotherapeutic agents, thus, making oxali-Pt an attractive

compound to be considered for the treatment against ovarian cancer. In addition, oxali-

36

demonstrate intrinsic and/or acquired cis-Pt resistance, such as in leukemia, colon,

ovarian cancer, breast, melanoma, bladder and glioma cancers [134].

2) Creation of different Pt isomers (cis vs. trans):

Pt compounds with trans geometry (that is, where X or L in [Pt(X)2(L)2] is in a

trans configuration) were initially proven to be inactive [135]. Pharmacokinetic studies

have shown that transplatin (trans-Pt) is highly reactive, with 70% of the drug

inactivated by conjugation with GSH after 4 hours incubation with red blood cells,

whereas only 35% of cis-Pt-GSH conjugate was formed in the same time [136]. The

rapid inactivation of trans-Pt by blood plasma components decreases the amount of

trans-Pt available to react with DNA and induce programed cell death. As a

consequence, the anticancer activity of trans-Pt is low. Recently, a new class of

modified trans-platinum (II) compounds, with chemical structure trans-[Pt(X)2(L)2] where

L= planar heterocyclic amine, have been reported to have novel activity profile against

different cancer cell lines. In addition, a group of trans-planar heterocyclic amine Pt (II)

compounds from the NCI were identified to be active against cis-Pt resistant cell lines,

suggesting that these compounds may be able to overcome cis-Pt mechanisms of

resistance [137]. One possible explanation could be in the difference of DNA adducts

formed by these Pt compounds. While cis-Pt and oxali-Pt mainly generate DNA damage

in the form of intrastrand crosslinks, trans-Pt compounds generate DNA interstrand

cross-links between the N7-Guanine and N3-Cytosine bases. These two types of

crosslinks are likely to activate intrinsic signaling pathway cascades, each leading to

37

characterization of these novel compounds should be conducted in order to identify their

potential for clinical development.

3) Changes on the oxidation state of the Pt atom:

Modification of Pt (II) to Pt (IV) compounds is achieved by increasing the

oxidation state of the Pt atom through the addition of two axial ligand groups, enabling

the formation of the tetrahedral chemical structure: [Pt(AL)2(X)2(L)2], where AL= axial

ligand. Axial ligands have been shown to play an essential role in the stability and

lipophillicity of Pt compounds [139]. In terms of stability, addition of axial ligands

significantly decrease the rate of reduction of Pt compounds in the bloodstream, thus,

promoting a decrease in the participation of the Pt compound in unwanted side

reactions, which leads to lower toxicity. Likewise, there will be an increase in the intact

levels of the activated Pt compound reaching its target site at the DNA; enabling a

higher cytotoxic activity. In addition, studies have revealed that different axial ligands

have different reduction potentials. For example, the reduction potential for the most

utilized axial ligands decreases as follows: chloro > carboxylate > hydroxyl.

Incorporation of axial ligands may also lead to higher lipophilicity of some Pt (IV)

complexes, which may improve the ability of the compound to cross the cell membrane

through passive diffusion, leading to an increase in cellular uptake [140]. Finally, the

activity of the Pt (IV) compound relies on its reduction to Pt (II), since it is the Pt (II)

complex which confers the cytotoxic mechanism of action [141]. The rational design of

Pt (IV) compounds from already proven active Pt (II) compounds may improve the compound’s stability, lipophilicity, enhancing its ability to circumvent cis-Pt resistance.

38

Indeed, the promising potential of Pt (IV) compounds can be appreciated by iproplatin,

tetraplatin, and JM216, which are Pt (IV) compounds that have entered clinical trials

39