René Maltais

René Maltais
Laval University | ULAVAL · Department of Molecular Medicine

Ph.D., Molecular Medicine
My interests are focused on development of novel therapeutics in oncology as well for inflammation related conditions

About

231
Publications
5,997
Reads
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1,170
Citations
Citations since 2017
57 Research Items
561 Citations
2017201820192020202120222023020406080100
2017201820192020202120222023020406080100
2017201820192020202120222023020406080100
2017201820192020202120222023020406080100
Introduction
I'm working in the field of medicinal chemistry, focusing on the design of new molecules targeting hormono-dependant and refractory cancers.
Additional affiliations
November 2011 - November 2014
Laval University
Position
  • Professor (Associate)
October 2006 - present
CHU de Québec Research Center
Position
  • Medicinal Chemist
Description
  • Chemical Synthesis, Steroids, Inhibitors, Breast cancer, Prostate cancer, endometriosis
January 2006 - December 2012
Education
September 1997 - May 2001
Laval University
Field of study
  • Molecular medecine

Publications

Publications (231)
Article
Full-text available
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays an important role in estrogen-dependent breast tumor growth. In addition to being involved in the production of estradiol (E2), the most potent estrogen in women, 17β-HSD1 is also responsible for the production of 5-androsten-3β,17β-diol (5-diol), a weaker estrogen than E2, but whose importan...
Article
Full-text available
Aminosteroid derivative RM-581 was previously identified as an endoplasmic-reticulum (ER) stress inducer with potent in vitro and in vivo anticancer activities. We report its evaluation in androgen-independent prostate cancer (PC-3) cells. RM-581 efficiently blocks PC-3 cell proliferation with stronger activity than that of a selection of known ant...
Patent
Full-text available
A method for the synthesis of specialized pro- resolving mediators, structural isomers thereof and analogs thereof is disclosed herein. The method comprises reacting a compd. of the formula (I) : (I) wherein R1 is alkyl(C≤12) , cycloalkyl(C≤12) , alkenyl(C≤12) , alkylidene(C≤12) , alkynyl(C≤12) , aryl, aralkyl, heteroaryl or heteroaralkyl; and X1,...
Article
Prostate cancer is the most common cancer among men and the development of new therapeutic agents is needed for its treatment and/or diagnosis. 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is involved in the production of androgens, which stimulates the proliferation of prostate cancer cells. Piperazinomethyl-androsterone sulfonamide derivati...
Article
Full-text available
Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrog...
Patent
Derivatives of 10S, 17S- diHDA (protectin DX, PDX) and medicinal uses thereof are disclosed. These derivatives are specialized pro- resolving mediators (SPRMs) . In specific embodiments, said derivatives. are used in to prevent or treat viral infections (including influenza and coronavirus infections) , insulin resistance, diabetes, and inflammator...
Patent
Full-text available
Novel chem. agents are described herein. More specifically, a novel inhibitor of 17β-HSD7 for decreasing estradiol concns. while restoring dihydrotestosterone (DHT) concns. in breast cancer cells is disclosed herein. In a particular embodiment, the inhibitor of 17β-HSD7 has the following structure: (Formula I) A process for producing the novel inhi...
Article
Endometriosis is a gynecological disorder affecting about 10% of women and can lead to invalidating painful symptoms and infertility. Since there is no current, definitive cure for this disease, new therapeutic options are necessary. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the production of estradiol (E2), the most potent...
Article
Full-text available
Aim and objective: The syntheses of glucuronide metabolites of phenolic xenoestrogens triclosan and 2-phenylphenol, namely triclosan-O-glucuronide (TCS-G; 1), and 2-phenylphenol-O-glucuronide (OPP-G; 2), were achieved for use as analytical standards. Methods: Under classical conditions previously reported for glucuronide synthesis, the final bas...
Article
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) and steroid sulfatase (STS) are involved in the synthesis of the most potent estrogen in the human body, estradiol (E2). These enzymes are known to play a pivotal role in the progression of estrogen-dependent diseases, such as breast cancer and endometriosis. Therefore, the inhibition of 17β-HSD1 a...
Article
RM-581 is an aminosteroid derivative comprised of a steroid core and a quinoline side chain showing potent cytotoxic activity on several types of cancer cells but for which the mechanism of action (MoA) remains to be fully elucidated. The opportunity to turn RM-581 into a fluorescent probe was explored because the addition of a N-dimethyl group was...
Article
A new androsterone derivative bearing a 16β-picolyl moiety (compound 5; FCO-586-119) was synthetized in four steps from the lead compound 1 (RM-532-105). We measured its inhibitory activity on 17β-HSD3 using microsomal fraction of rat testes as well as transfected LNCaP[17β-HSD3] cells. We then assessed its metabolic stability as well as its cytoto...
Article
Full-text available
The combination of an androstane-3,17-diol nucleus and a 2β-N-alkylamidopiperazino sidechain is important for the anticancer activity of a new family of steroid derivatives. As the structure-activity relationship studies have so far been limited to the beta orientation of the substituent at position 2 of the steroid nucleus, a series of analogs (co...
Article
17beta-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is the only mitochondrial member of 17β-HSD family. This enzyme can oxidize estradiol (E2) into estrone (E1), thus reducing concentration of this neuroprotective steroid. Since 17β-HSD10 possesses properties that suggest a possible role in Alzheimer’s disease, its inhibition appears to be a th...
Article
Background The last step in the production of androgen testosterone from 4-androstene-3,17-dione (4-dione) in testis involves the 17-hydroxysteroid dehydrogenase type 3 (17-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent...
Article
Steroid sulfatase (STS) is an important enzyme regulating the conversion of sulfated steroids into their active hydroxylated forms. Notably, the inhibition of STS has been shown to decrease the levels of active estrogens and was translated into clinical trials for the treatment of breast cancer. Based on quantitative structure-activity relationship...
Article
The use of new aminosteroids has shown increased therapeutic efficiency on multiple cancer cell lines. Those molecules are, however, highly hydrophobic, leading to bad pharma-cokinetic properties. Dendrimers are excellent candidates to improve PK, especially for absorption and distribution, since their structure can be designed to be water-soluble....
Article
The use of new aminosteroids has shown increased therapeutic efficiency on multiple cancer cell lines. Those molecules are, however, highly hydrophobic, leading to bad pharmacokinetic properties. Dendrimers are excellent candidates to improve PK, especially for absorption and distribution, since their structure can be designed to be water‐soluble....
Article
The aminosteroid (AM) RM-581 is built around a mestranol backbone and has recently emerged as this family's lead candidate, showing in vitro and in vivo potency over different types of cancer, including high fatality pancreatic cancer. To extend the structure-activity relationships (SAR) to other estrane analogs, we synthesized a focused series of...
Article
5α-Dihydrotestosterone (5α-DHT) possesses a great affinity for the androgen receptor (AR), and its binding to AR promotes the proliferation of prostate cancer (PC) cells in androgen-dependent PC. Primarily synthesized from testosterone (T) in testis, 5α-DHT could also be produced from 5α-androstane-3α,17β-diol (3α-diol), an almost inactive androgen...
Article
Efforts toward the development of a reliable gram scale synthesis of PBRM, a potent and selective steroidal covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), are described. Among the three synthetic routes (C-E) developed herein, route E is the most efficient one with only 6 chemical steps from commercially available estrone...
Article
Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a strategy to treat prostate cancer. The androsterone (ADT) derivative 1 (RM-532-105) has shown strong inhibitory activity on 17β-HSD3, but needs to be improved. Herein, we describe the chemical synthesis and characteriza...
Presentation
The first total synthesis of a lipid mediator derived from natural omega-3-fatty acid docosahexaenoic acid (DHA), 10S,17S-diHDHA (also referred to as protectin DX/PDX) was achieved in a convergent route (29 steps). The two chiral hydroxyl groups at C-10 and C-17 were derived from readily available (S)-1,2,4-butanetriol and (R)-glycidol, respectivel...
Presentation
Cancer is responsible for one in four deaths in Canada. In fact, despite the large number of available cancer-treating drugs, new ones, acting differently by different mechanisms, need to be developed to overcome drug resistance and improve overall survival rate. Based on structure-activity relationship (SAR) studies, we developed two closely relat...
Conference Paper
Full-text available
Aminosteroid (AM) derivatives are a new family of pro-apoptotic anticancer compounds inducing endoplasmic reticulum stress via disturbance of cholesterol homeostasis. RM-581, built around a mestranol backbone, has recently emerged as the lead candidate of this family and shown in vitro and in vivo potency over different cancer types, including high...
Conference Paper
Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a strategy to treat prostate cancer. The androsterone (ADT) derivative 1 (RM-532-105) has shown strong inhibitory activity on 17β-HSD3, but needs to be improved. Herein, we describe the chemical synthesis of two series of...
Presentation
The development of a reliable multigram synthesis of PBRM, a potent and selective steroidal covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), has been efficiently achieved. Among the four synthetic routes (A-D) developed, route D is by far the most efficient one with only 6 chemical steps from commercially available estrone,...
Article
Full-text available
The high fatality and morbidity of pancreatic cancer have remained almost unchanged over the last decades and new clinical therapeutic tools are urgently needed. We determined the cytotoxic activity of aminosteroid derivatives RM-133 (androstane) and RM-581 (estrane) in three human pancreatic cancer cell lines (BxPC3, Hs766T and PANC-1). In PANC-1,...
Conference Paper
Les dérivés d'aminostéroïdes (AM) constituent une nouvelle famille de composés anticancéreux pro-apoptotiques induisant un stress du réticulum endoplasmique (RE) via une perturbation de l'homéostasie du cholestérol. Le RM-581, construit autour d'un squelette de mestranol, est récemment devenu le candidat principal de cette famille et a démontré de...
Presentation
La stéroide sulfatase (STS) est une enzyme clé impliquée dans la biosynthèse des estrogènes et des androgènes car elle catalyse l’hydrolyse des stéroïdes sulfatés (CHOLS, DHEA-S, PREG-S, E1-S et E2-S) en leurs correspondants non sulfatés, précurseurs des hormones actives. De ce fait, la STS constitue une cible thérapeutique intéressante pour traite...
Conference Paper
Le cancer du sein est le cancer le plus fréquent chez les femmes, à l'exception des cancers de la peau et la deuxième cause de décès par cancer. Parmi les patientes atteintes du cancer du sein, environ 65% ont un cancer hormono-dépendant, ce qui signifie que plus de la moitié des cancers du sein sont susceptibles de réagir positivement à un traitem...
Article
Steroid sulfatase (STS) is a key enzyme involved in the biosynthesis of estrogens from inactive sulfated steroids. After we reported EO-33 as a potent in vitro STS inhibitor without undesirable estrogenic activity and with osteogenic properties, we are now interested in validating EO-33’s in vivo potential to inhibit STS, to prevent bone deteriorat...
Article
Full-text available
The first total synthesis of a lipid mediator derived from natural ω-3-fatty acid docosahexaenoic acid (DHA), 10S,17S-diHDHA (also referred to as protectin DX/PDX), was achieved in a convergent route (29 steps). The two chiral hydroxyl groups at C-10 and C-17 were derived from readily available (S)-1,2,4-butanetriol and (R)-glycidol, respectively....
Article
Cytochrome P450 (CYP) 1B1 is involved in the bioactivation of procarcinogens and drug-resistance. To obtain selective CYP1B1 inhibitors overs CYP1A1, we synthesized four series of estrane derivatives: 1) twelve estrone (E1)- and 17β-estradiol (E2)-derivatives bearing a 3- or a 4-pyridinyl core at C2, C3, or C4, 2) eight estrane derivatives with dif...
Article
17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known for its potential role in Alzheimer's Disease (AD). 17β-HSD10, by its oxidative activity, could decrease the concentration of two important neurosteroids, allopregnanolone (ALLOP) and 17β-estradiol (E2), respectively preventing their neurogenesis and neuroprotectiv...
Article
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a promising therapeutic target known to play a pivotal role in the progression of estrogen-dependent diseases such as breast cancer, and endometriosis. This enzyme is responsible for the last step in the biosynthesis of the most potent estrogen, estradiol (E2) and its inhibition would prevent th...
Article
17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) plays a pivotal role in the progression of estrogen-related diseases due to its involvement in the biosynthesis of estradiol (E2), constituting a valuable therapeutic target for endocrine treatment. In the present study, we successfully co-crystallized the enzyme with the reversible inhibitor 2-met...
Article
Background: RM-133 belongs to a new family of aminosteroid derivatives demonstrating interesting anticancer properties, as confirmed in vivo in four mouse cancer xenograft models. However, the metabolic stability of RM-133 needs to be improved. After investigation, the replacement of its androstane scaffold by a more stable estrane scaffold led to...
Article
The development of a covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a promising approach for the treatment of hormone-dependent breast cancer and endometriosis. After reporting the steroid derivative PBRM as a first potent covalent inhibitor of 17β-HSD1 without estrogenic activity, we are now interested in studying its...
Article
Full-text available
The fortuitous modification of a quinoline-proline-piperazine side chain linked to a steroid in the presence of lithium (trimethylsilyl) acetylide has generated an unknown product that is more active than its precursor. After having characterized two β-enaminones (two-carbon homologation compounds) that were generated from a simplified model side c...
Conference Paper
Prostate Cancer (PCa) has been a major public health concern in North America since it is the second most common cancer in men. Although there are currently several hormonal therapies to improve health or prolong life expectancy, PCa often evolves into a resistant form. The androgen receptor (AR) signaling pathway plays a central role in PCa develo...
Article
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-{[(16β,17β)-3-(2-bromoethyl)-17-hydroxyestra-1,3,5(10)-trien-16-yl]methyl} benzamide (PBRM),...
Article
Full-text available
In the fight against androgen-sensitive prostate cancer, the enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an attractive therapeutic target considering its key role in the formation of androgenic steroids. In this study, we attempted to assess the in vivo efficacy of the compound RM-532-105, an androsterone derivative developed as an...
Article
17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a major player in human endocrinology, being one of the most important enzymes involved in testosterone production. To capitalize on the discovery of RM-532-105, a steroidal 17β-HSD3 inhibitor, we explored the effect of its backbone configuration on inhibitory activity, androgenic profile, and m...
Article
Anticancer structure-activity relationship studies on aminosteroid (5α-androstane) derivatives have emerged with a promising lead candidate: RM-133 (2β-[1-(quinoline-2-carbonyl)pyrrolidine-2-carbonyl]-N-piperazine-5α-androstane-3α,17β-diol), which possesses high in vitro and in vivo activities against several cancer cells, and selectivity over norm...
Article
RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-act...
Patent
Full-text available
Estrane- based and androstane- based aminosteroid derivs. of formula I [A = C, (substituted) N; B = CO, SO2, CH2, etc.; R1 = OH, halo, alkoxy, acyloxy, etc.; R2 = H, halo, OH, alkoxy, methoxymethoxy, etc.; R3 = H2, O; Z = H, halo, C≡CH, etc.; V = amino acid, etc.; W = CO, SO2, CONH, etc.; X = alkyl, alkoxy, alkylthio, aryl, aryloxy, cycloalkyl, het...
Article
Steroid sulfatase (STS), the enzyme which converts inactive sulfated steroid precursors into active hormones, is a promising therapeutic target for the treatment of estrogen-sensitive breast cancer. We report herein the synthesis and in vitro study of dual-action STS inhibitors with selective estrogen-receptor modulator (SERM) effects. A library of...
Article
The steroidogenic enzyme 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a therapeutic target in the management of androgen-sensitive diseases such as prostate cancer and benign prostate hyperplasia. In this paper, we designed and synthesized the first fluorescent inhibitor of this enzyme by combining a fluorogenic dansyl moiety to the chemic...
Article
Full-text available
Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new d...
Data
Table A. RM-133 solubility in 11 injection vehicles; Table B. Effect of a single s.c. injection of 8 vehicles in mice behavior; Table C. Effect of repeated s.c. injections of RM-133 using 3 preselected vehicles. (PDF)
Article
Steroids possessing an ethynyl group at position 17α (tertiary alcohols) are well known to be more stable than their non-ethynyl analogs (secondary alcohols). To facilitate the development of new drugs with better metabolic stability, we developed a new diethylsilyl acetylenic linker allowing us to rapidly synthesize libraries of ethynylated steroi...
Article
The chemical synthesis of four stereoisomers (compounds 5a-5d) of 16β-(m-carbamoylbenzyl)-estradiol, a potent reversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), and two intermediates (compounds 3a and 3b) was performed. Assignment of all nuclear magnetic resonance signals confirmed the stereochemistry at positions 13, 16 an...
Article
17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a key enzyme involved in the biosynthesis of testosterone and dihydrotestosterone. These hormones are known to stimulate androgen-dependent prostate cancer. In order to generate effective inhibitors of androgen biosynthesis without androgenic effect, we synthesized a new family of 3-spiromorphol...
Patent
Provided are compounds of general formula A and A', wherein X1 and X2 are each C, CH or N; R3 and R4 are each H, optionally substituted C1-C30 saturated or unsaturated chemical group, or together form an optionally substituted C5-C8 cycle; Z1; Z2 and Z3 are each N or CH; V is C=0, C=S or CH2; n is from 1 to 12; W1 and W2 are each H, CH2, O or S; an...
Article
Full-text available
The steroid derivative EM-1913 is a non-estrogenic inhibitor of steroid sulfatase (STS), an enzyme involved in the biosynthesis of estrogens and androgens. As an approach to treat estrogen-dependent diseases such as breast cancer, we want to test EM-1913 in an estrogen-dependent breast cancer tumor model in vivo. Ovariectomized nude mice were inocu...