Roberto Martínez

The Search of DNA-Intercalators as Antitumoral Drugs: What it Worked and What did not Work

The discovery of new compounds with antitumoral activity has become one of the most important goals in medicinal chemistry. One interesting group of chemotherapeutic agents used in cancer therapy comprises molecules that interact with DNA. Research in this area has revealed a range of DNA recognizing molecules that act as antitumoral agents, including groove binders, alkylating and intercalator compounds. DNA intercalators (molecules that intercalate between DNA base pairs) have attracted particular attention due to their antitumoral activity. For example, a number of acridine and anthracycline derivatives are excellent DNA intercalators that are now on the market as chemotherapeutic agents. Commercially available acridine and anthracycline derivatives have been widely studied from a variety of viewpoints, such as physicochemical properties, structural requirements, synthesis and biological activity. However, the clinical application of these and other compounds of the same class has encountered problems such as multidrug resistance (MRD), and secondary and/or collateral effects. These shortcomings have motivated the search for new compounds to be used either in place of, or in conjunction with, the existing compounds. Unfortunately, the results of this search have not met expectations. The vast majority of candidate intercalator compounds tested for use as anticancer agents have shown little or no biological activity. Research in this area has not been without benefits, however, for it has produced much information on the synthesis and antitumoral properties of hundreds of compounds, which have been tested on diverse tumoral cell lines. This review considers the structural and biological considerations relevant to the use of DNA intercalators and bis-intercalators as antitumoral agents, with an emphasis on the relationship between structure and activity, produced in last decade.

Universality of Rank-Ordering Distributions in the Arts and Sciences

Searching for generic behaviors has been one of the driving forces leading to a deep understanding and classification of diverse phenomena. Usually a starting point is the development of a phenomenology based on observations. Such is the case for power law distributions encountered in a wealth of situations coming from physics, geophysics, biology, lexicography as well as social and financial networks. This finding is however restricted to a range of values outside of which finite size corrections are often invoked. Here we uncover a universal behavior of the way in which elements of a system are distributed according to their rank with respect to a given property, valid for the full range of values, regardless of whether or not a power law has previously been suggested. We propose a two parameter functional form for these rank-ordered distributions that gives excellent fits to an impressive amount of very diverse phenomena, coming from the arts, social and natural sciences. It is a discrete version of a generalized beta distribution, given by f(r) = A(N+1-r)b/ra, where r is the rank, N its maximum value, A the normalization constant and (a, b) two fitting exponents. Prompted by our genetic sequence observations we present a growth probabilistic model incorporating mutation-duplication features that generates data complying with this distribution. The competition between permanence and change appears to be a relevant, though not necessary feature. Additionally, our observations mainly of social phenomena suggest that a multifactorial quality resulting from the convergence of several heterogeneous underlying processes is an important feature. We also explore the significance of the distribution parameters and their classifying potential. The ubiquity of our findings suggests that there must be a fundamental underlying explanation, most probably of a statistical nature, such as an appropriate central limit theorem formulation.

Cavernomas of the spinal cord: report of two cases.

Two cases of intramedullary cavernomas are presented. Both patients showed progressive neurological deficit. Cavernoma must be considered in the differential diagnosis of spinal cord tumors.

Recurrence in a different location of a cerebral arteriovenous malformation in a child after radiosurgery

Abstract The case of a 9-year-old girl with a right parietal arteriovenous malformation (AVM) of the brain obliterated after gamma knife (GK) radiosurgery with subsequent regrowth in a different site is reported. As far as we know, this is the first reported case of regrowth of an AVM in a different location after radiosurgery in a child. This situation has to be considered within the context of causes of unsuccessful treatment of AVMs with radiosurgery and justifies angiographic monitoring of pediatric patients until they reach adulthood.

Symptomatic glial cysts of the pineal gland

Two cases of symptomatic glial cysts of the pineal gland are reported. An origin similar to that proposed for paraventricular glial cysts of the brain is accepted. These unusual lesions could be considered in the differential diagnosis of cystic pineal masses.

Convexity Meningioma and Glioblastoma in Collision

An unusual case of benign convexity meningioma and glioblastoma in collision is presented. The preoperative diagnosis of this association is difficult to make based on symptomatology or computed tomography scans alone. This case supports the possibility of a malignant transformation within the gliosis surrounding a convexity meningioma.

Traumatic false aneurysms of the middle meningeal artery.

The authors report a rare case of traumatic false aneurysm of the middle meningeal artery associated with a delayed contralateral extradural hematoma. The extradural hematoma was evacuated, and the pseudoaneurysm was removed to avoid delayed rupture. The literature on traumatic aneurysms is reviewed.

Stereotactic biopsy for brain tumors: is it always necessary?

BACKGROUND Stereotactic biopsy is currently being used in oncological neurosurgery despite its limitations. The purpose of this study is to compare its diagnostic reliability with that of the diagnosis based on clinical data and neuroimaging techniques. METHODS We studied 200 patients (134 men and 66 women) who underwent 212 stereotactic biopsy procedures to assess brain tumors. All were subjected to CT scan and 71 patients also underwent MRI. A presumptive diagnosis of brain tumor was established in each case and the findings compared with the results of stereotactic biopsy and the clinical course. RESULTS A clear presumptive diagnosis was established before stereotactic biopsy in 90% of the patients, and in 95% of this group, the diagnosis was confirmed by the biopsy and/or the clinical course. The stereotactic biopsy modified the presumptive diagnosis in eight patients (4%), without changing the clinical diagnosis of malignant lesion. In our present series, 10% of the procedures were of no help in determining a diagnosis and in 7% of patients, the stereotactic biopsy led to diagnostic errors that influenced the therapeutic management and resulted in an erroneous prognosis. CONCLUSIONS These data confirm the need for clinical correlation with the findings obtained at stereotactic biopsy and suggest that stereotactic biopsy may not always be useful or necessary in the management of brain tumor patients. According to our present critical analysis, when a clear presumptive diagnosis of brain tumor can be made, it may be sufficient to base the management of the patient only on clinical and neuroimaging findings.

Synthesis and in vitro cytotoxic activity of pyrrolo[2,3-e]indole derivatives and a dihydro benzoindole analogue.

The synthesis of pyrrolo[2,3-e]indole derivatives with the structural characteristics of DNA bis- and mono-intercalators are described. A dihydro benzoindol analogue was also synthesised to elucidate the major structural requirements for cytotoxic activity. A biological evaluation of the test compounds was carried out in six different tumoral cell lines. The factors that affect the cytotoxic activity appear to be the substituents on the phenyl group, the presence of an amide group capable of strong interactions such as hydrogen bonding and solubility.

A SIMPLE METHOD FOR THE SYNTHESIS OF CARBAMATES

Abstract A new method for carbamate synthesis using aryl and alkylamines with sodium hydride and diethylcarbonate in dry benzene is described.