Synthesis of N-acyl Derivatives of Aminocombretastatin A-4 and Study of their Interaction with Tubulin and Downregulation of c-Myc.

Background: Six N-acyl derivatives of aminocombretastatin A-4 have been synthesized and evaluated according to their interaction with tubulin and as c-Myc downregulators.

Aims: In search of new promising anti-cancer agents.

Objective: This study is focused on the synthesis and the biological evaluation of N-acyl derivatives of aminocombretastatin A-4 (CA-4).

Synthesis of Combretastatin A-4 and 3'-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of Their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression.

Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3'-aminocombretastatin A-4 (AmCA-4) have shown promising antitumor activities. In this study, a range of CA-4 and AmCA-4 derivatives containing amino acid pendants have been synthesized in order to compare their biological actions with those of their parent compounds. Thus, inhibition of cell proliferation on tumor cell lines HT-29, MCF-7 and A-549, as well as on the nontumor cell line HEK-273; in vitro tubulin polymerization; mitotic cell arrest; action on the microtubule cell network and inhibition of VEGF, hTERT, and c-Myc genes have been evaluated.

N-alpha-Aminoacyl Colchicines as Promising Anticancer Agents.

Background: In the last years, many efforts have been made to find colchicine derivatives with reduced toxicity. Additionally, the deregulation of amino acid uptake by cancer cells provides an opportunity to improve anticancer drug effectiveness.

Objective: To design new colchicine derivatives with reduced cytotoxicity and enhanced selectivity by means of introducing aminoacyl groups.

Arylpyridines, arylpyrimidines and related compounds as potential modulator agents of the VEGF, hTERT and c-Myc oncogenes.

Twenty-four derivatives structurally related to honokiol have been synthesized and biologically evaluated. IC values were determined towards the HT-29, MCF-7 and HEK-293 cell lines. Some of these derivatives exhibited comparable or lower IC values than honokiol towards the HT-29 and MCF-7 cell lines or else higher selectivity indexes than the natural product.

Synthesis and biological evaluation as antiangiogenic agents of ureas derived from 3'-aminocombretastatin A-4.

Twenty-six compounds derived from 3'-aminocombretastatin A-4 (AmCA-4) containing a urea fragment mimicking the structure of Sorafenib, have been synthesized and evaluated as antiangiogenic compounds. Antiproliferative activity of all the synthetic ureas has been measured on tumor cell lines HT-29, MCF-7, HeLa, A-549 and HL-60 as well as on the endothelial cell line HMEC-1 and on the non-tumor cell line HEK-293. Preliminary docking studies were developed in order to predict which ureas show better interactions with the protein VEGFR-2.

Effect of frame rate capture frequency on sperm kinematic parameters and subpopulation structure definition in boars, analysed with a CASA-Mot system.

Motility is the most widely used indicator of sperm quality. Computer-Assisted Semen Analysis (CASA) allows the objective evaluation of sperm motility parameters. CASA technology is a common tool to predict semen doses in farm animal reproduction.

Synthesis and biological evaluation of cyclic derivatives of combretastatin A-4 containing group 14 elements.

Several tricyclic compounds inspired by the structure of combretastatin A-4 and bearing group 14 elements have been synthesized by homocoupling lithiated aryl fragments followed by ring-closing metathesis. These tricyclic compounds and their diolefin precursors were evaluated for their antiproliferative action on the tumor cell lines HT-29, MCF-7, HeLa and A-549 and on the non-tumor cell line HEK-293. In addition, their effects on the cell cycle were also measured.

Arylureas derived from colchicine: Enhancement of colchicine oncogene downregulation activity.

Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty-seven N,N'-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of the compounds, their ability to inhibit the expression of oncogenes related to telomerase activation and to the VEGF/VEGFR-2 autocrine process, such as c-MYC, hTERT and VEGF and their capability to downregulate c-MYC and VEGFR-2 proteins and the secretion of VEGF have been measured. In these biological evaluations, we have found that the change of the acetyl group in colchicines for an N-arylurea unit causes a great improvement in anticancer properties.

Effects on tubulin polymerization and down-regulation of c-Myc, hTERT and VEGF genes by colchicine haloacetyl and haloaroyl derivatives.

Several colchicine analogues in which the N-acetyl residue has been replaced by haloacetyl, cyclohexylacetyl, phenylacetyl and various aroyl moieties have been synthesized. The cytotoxic activities of the synthesized compounds have been measured on three tumor cell lines (HT-29, MCF-7 and A549) and on one non-tumor cell line (HEK-293). These compounds exhibit high antiproliferative activities at the nanomolar level, in many cases with a higher potency than colchicine itself.

Synthesis and biological evaluation of carbamates derived from aminocombretastatin A-4 as vascular disrupting agents.

A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptosis and endothelial tubular structures in vitro. The anti-proliferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e.

Synthesis and Biological Evaluation of Imines Structurally Related to Resveratrol as Dual Inhibitors of VEGF Protein Secretion and hTERT Gene Expression.

A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resveratrol has been prepared through condensation of anilines with the corresponding aldehydes. The ability of these imines to inhibit proliferation of two tumor cell lines (HT-29 and MCF-7) and one non-tumor cell line (HEK- 293) was first determined. Subsequently, we determined the ability of some of the most cytotoxic compounds to inhibit the secretion of the VEGF-A factor in HT-29 cells and to downregulate the expression of the VEGF and hTERT genes, the latter one being involved in the activation of telomerase.

Interactions of long-chain homologues of colchicine with tubulin.

Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straight-chain acyl moieties, have been synthesized. These compounds show high cytotoxic activity at the nanomolar level against the tumoral cell lines HT-29, MCF-7 and A549. Some of them exhibit activities in the picomolar range against the HT-29 line and are thus two to three orders of magnitude more cytotoxic than colchicine.

Synthesis and biological evaluation of simplified pironetin analogues with modifications in the side chain and the lactone ring.

The preparation of several new analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the nature of the side chain and the lactone ring. Their cytotoxic activity has been measured.

Synthesis of honokiol analogues and evaluation of their modulating action on VEGF protein secretion and telomerase-related gene expressions.

A group of 36 biphenyl derivatives structurally related to honokiol were synthesized by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT, and c-Myc genes; the two latter involved in the activation of telomerase in tumoral cells.

Pironetin Binds Covalently to αCys316 and Perturbs a Major Loop and Helix of α-Tubulin to Inhibit Microtubule Formation.

Microtubule-targeting agents are among the most powerful drugs used in chemotherapy to treat cancer patients. Pironetin is a natural product that displays promising anticancer properties by binding to and potently inhibiting tubulin assembly into microtubules; however, its molecular mechanism of action remained obscure. Here, we solved the crystal structure of the tubulin-pironetin complex and found that the compound covalently binds to Cys316 of α-tubulin.

Synthesis and evaluation of biphenyl derivatives as potential downregulators of VEGF protein secretion and telomerase-related gene expressions.

A group of 47 biphenyl functionalized compounds, prepared by means of Suzuki couplings, has been investigated for their cytotoxicity on two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293). 29 selected compounds have been investigated for their ability to inhibit the production of the vascular endothelial growth factor (VEGF). Subsequently, the capacity of the compounds to downregulate the expression of the VEGF, h-TERT and c-Myc genes, the two latter involved in the control of the activation of telomerase, has also been determined.

Inhibitory effect of cytotoxic stilbenes related to resveratrol on the expression of the VEGF, hTERT and c-Myc genes.

A group of thirty-nine stilbene derivatives, prepared by means of Heck coupling reactions, has been investigated for their cytotoxicity, as well as for their ability to inhibit the production of the vascular endothelial growth factor (VEGF) and the activation of telomerase. The ability of these compounds to inhibit proliferation of two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293) was first determined. Subsequently, we determined the capacity of the compounds to inhibit the secretion of VEGF in the aforementioned cell lines and to downregulate the expression of the VEGF, hTERT and c-Myc genes, the two latter involved in the control of the activation of telomerase.

Inhibitory effect of pironetin analogue/colchicine hybrids on the expression of the VEGF, hTERT and c-Myc genes.

A small group of hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment have been investigated for their ability to inhibit the expression of the VEGF, hTERT and c-Myc genes. The VEGF gene is involved in the generation of the vascular endothelial growth factor (VEGF) and thus in the angiogenic process whereas the two latter ones are related to the activation of telomerase. All three genes therefore may be of paramount importance in the cancer generation process.

The Mechanism of the Interactions of Pironetin Analog/Combretastatin A-4 Hybrids with Tubulin.

We here report an investigation of the interactions with tubulin of two types of molecules of a hybrid structural type consisting in a combretastatin A-4 moiety and a simplified pironetin fragment. The cytotoxicities of the molecules on two reference tumoral cell lines were measured. In addition, the effects of the compounds on the cell cycle and on microtubule assembly were observed.

Design and synthesis of pironetin analogue/colchicine hybrids and study of their cytotoxic activity and mechanisms of interaction with tubulin.

We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an ester-amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated.

Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer.

Background: Antibody-drug conjugates (ADCs) are an emerging class of cancer therapies that have demonstrated favorable activity both as single agents and as components of combination regimens. Phase 2 testing of an ADC targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer has shown antitumor activity. The present study examined PSMA ADC used in combination with potent antiandrogens (enzalutamide and abiraterone) and other compounds.

Design and synthesis of pironetin analogue/combretastatin A-4 hybrids containing a 1,2,3-triazole ring and evaluation of their cytotoxic activity.

We here describe the preparation of a series of hybrid molecules containing a combretastatin A-4 moiety and a pironetin analogue fragment connected through a spacer of variable length which includes a 1,2,3-triazole ring. The cytotoxic activities of these compounds have been measured. Relations between structure and cytotoxicity are discussed.

Synthesis of combretastatin A-4 O-alkyl derivatives and evaluation of their cytotoxic, antiangiogenic and antitelomerase activity.

We here report the synthesis and biological evaluation of several combretastatin A-4 derivatives alkylated at the phenol hydroxyl group. Some of these derivatives contain an (E)-arylalkene fragment reminiscent of that present in some natural stilbenes like resveratrol. The cytotoxicities towards one human healthy kidney embryonic and two tumoral cell lines were determined.

Synthesis and biological evaluation of truncated α-tubulin-binding pironetin analogues lacking alkyl pendants in the side chain or the dihydropyrone ring.

The preparation of several new truncated analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the suppression of some of the alkyl pendants in either the side chain or the dihydropyrone ring. Their cytotoxic activity and their interactions with tubulin have been investigated.