Discovery of Steroidal Lactam Conjugates of POPAM-NH
            <sub>2</sub>
            With Potent Anticancer Activity

Trafalis, Dimitrios T.; Dalezis, Panagiotis; Geromichalou, Elena; Sagredou, Sofia; Sflakidou, Eleni; Voura, Maria; Grammatikopoulou, Margarita; Gabriel, Catherine; Sarli, Vasiliki

doi:10.4155/fmc-2019-0255

Cited by 6 publications

(7 citation statements)

References 42 publications

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“…These hybrid molecules were aimed to increase anticancer activity, reduce systemic toxicity, and improve the overall therapeutic ratio. Furthermore, LSAs induce a multi-targeted antitumor effect by inhibiting the function of critical cellular pathways important for cancer cell survival cancer cells [7][8][9][10][11][12][22][23][24][25].…”

Section: Discussionmentioning

confidence: 99%

“…Cells were plated in 96-well plate at a density of 1 × 10 4 cells/mL per well and maintained for 72 h at 37 • C in a 5% CO 2 incubator and grown as monolayers. After 24 h, cells were treated with 0.1-100 µmol/L of the tested compounds for 48 h. The viability of cultured cells was estimated by utilizing the (3-(4,5-imethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay, as described previously [23,24]. Briefly, MTT (Sigma, St Louis, Missouri, USA) was dissolved in PBS in a concentration of 5 mg/mL, filter sterilized, and stored at 4 • C. Then, 50 µL of stock solution was added to each culture and incubated for 3 h at 37 • C. Formazan crystals were solubilized by DMSO (100 µL).…”

Section: Determination Of Cell Viability By the Mtt Assaymentioning

confidence: 99%

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Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

Dalezis

Geromichalou

Polonifi

et al. 2020

Cancers

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(1) Background: Previous findings show that lactam steroidal alkylating esters display improved therapeutic efficacy with reduced toxicity. The aim of this study was to evaluate the anticancer activity of two newly synthesized aza-steroid alkylators (ENGA-L06E and ENGA-L08E) against human ovarian carcinoma cells, and consequently, the dual inhibition of RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways, both of which are closely associated with ovarian cancer; (2) Methods: The in vitro cytostatic and cytotoxic effects of ENGA-L06E and ENGA-L08E were evaluated in a panel of five human ovarian cancer cell lines, as well as in in vivo studies. ENGA-L06E and ENGA-L08E, in addition to another two aniline-mustard alkylators, POPAM and melphalan (L-PAM), were utilized in order to determine the acute toxicity and antitumor efficacy on two human ovarian xenograft models. Also, in silico studies were performed in order to investigate the dual inhibition of ENGA-L06E and ENGA-L08E on RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways; (3) Results: Both, in vitro and in vivo studies demonstrated that ENGA-L06E and ENGA-L08E were significantly more effective with a lower toxicity profile in comparison to POPAM and L-PAM alkylators. Moreover, in silico studies demonstrated that the two new aza-steroid alkylators could act as efficient inhibitors of the phosphorylation of AKT and ERK1/2 molecules; and (4) Conclusions: Both ENGA-L06E and ENGA-L08E demonstrated high anticancer activity through the inhibition of the PI3K-AKT and KRAS-ERK signaling pathways against human ovarian carcinoma, and thus constituting strong evidence towards further clinical development.

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Section: Discussionmentioning

confidence: 99%

Section: Determination Of Cell Viability By the Mtt Assaymentioning

confidence: 99%

Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

Dalezis

Geromichalou

Polonifi

et al. 2020

Cancers

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“…These results further confirm that the hybrid aza-steroid alkylators are overcoming relevant cell drug resistance pharmacological mechanisms. Moreover, these chimeric compounds, that bear a modified steroid containing a lactamic group (-NH-C=O−) and carry an alkylating moiety, produce a higher antitumor activity than other alkylators conventionally used in cancer therapy [16,22,24,39,40,43,44].…”

Section: Discussionmentioning

confidence: 99%

“…Three lactamic homo-aza-steroidal alkylators-the B-lactam-steroid alkylator (derived from dehydroepiandrosterone), namely 7a,9a-dimethyl-2,10-dioxo-1,2,4,5,6,7,7a,7b, 8,9,9a, 10,11, 12,12a,12b-hexadecahydrobenzo[d]indeno [4,5-b]azepin-5-yl 3-(4-(bis(2-chloroethyl)amino) phenoxy)propanoate (ASA-A), the B,D-homo-aza (bilactam)-steroid alkylator (derived from dehydroepiandrosterone), namely 11a,13a-dimethyl-2,6-dioxo-2,3,4,4a,4b,5,6,8,9,10,11,11a, 11b,12,13,13a-hexadecahydro-1H-benzo [4,5]azepino [2,3-f]quinolin-9-yl 3-(4-(bis(2-chlor oethyl)amino)phenoxy)propanoate (ASA-B), and the B-homo-aza (lactam)-alkylator derived from 5-cholesten-3b-ol-7-one (ASA-C), namely 7a,9a-dimethyl-10-((R)-6-methylheptan-2-yl)-2-oxo-1,2,4,5,6,7,7a,7b,8,9,9a, 10,11,12,12a,12b-hexadecahydrobenzo[d]indeno [4,5-b] azepin-5-yl 3-(4-(bis(2-chloro ethyl)amino)phenoxy)propanoate were synthesized and prepared according to previously described methods and procedures (Figure 1) [17,[22][23][24]. All three alkylating B-lactam steroidal esters were esterified with the alkylating nitrogen mustard 3-(4-(bis(2-chloroethyl)amino)phenoxy)propanoic acid (POPA).…”

Section: Compoundsmentioning

confidence: 99%

Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay

et al. 2021

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We evaluated three newly synthesized B-lactam hybrid homo-aza-steroidal alkylators (ASA-A, ASA-B and ASA-C) for their PARP1/2 inhibition activity and their DNA damaging effect against human ovarian carcinoma cells. These agents are conjugated with an alkylating component (POPA), which also served as a reference molecule (positive control) and were tested against four human ovarian cell lines in vitro (UWB1.289 + BRCA1, UWB1.289, SKOV-3 and OVCAR-3). The studied compounds were thereafter compared to 3-AB, a known PARP inhibitor, as well as to Olaparib, a standard third-generation PARP inhibitor, on a PARP assay investigating their inhibitory potential. Finally, a PARP1 and PARP2 mRNA expression analysis by qRT-PCR was produced in order to measure the absolute and the relative gene expression (in mRNA transcripts) between treated and untreated cells. All the investigated hybrid steroid alkylators and POPA decreased in vitro cell growth differentially, according to the sensitivity and different gene characteristics of each cell line, while ASA-A and ASA-B presented the most significant anticancer activity. Both these compounds induced PARP1/2 enzyme inhibition, DNA damage (alkylation) and upregulation of PARP mRNA expression, for all tested cell lines. However, ASA-C underperformed on average in the above tasks, while the compound ASA-B induced synthetic lethality effects on the ovarian cancer cells. Nevertheless, the overall outcome, leading to a drug-like potential, provides strong evidence toward further evaluation.

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“…Additionally, encouraging results were obtained for the steroidal phenylacetic acid mustard conjugate on primary inoperable incurable breast cancer in a phase I study . Subsequently plenty of research was carried out in this area in the past two decades by synthesizing hydrolyzable ester linked steroid–nitrogen mustard conjugates. − …”

Section: Therapeutic Potential Of Steroidal Bioconjugatesmentioning

confidence: 99%

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

Bansal

Suryan

2022

ACS Bio Med Chem Au

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Ever increasing unmet medical requirements of the human race and the continuous fight for survival against variety of diseases give birth to novel molecules through research. As diseases evolve, different strategies are employed to counter the new challenges and to discover safer, more effective, and target-specific therapeutic agents. Among several novel approaches, bioconjugation, in which two chemical moieties are joined together to achieve noticeable results, has emerged as a simple and convenient technique for a medicinal chemist to obtain potent molecules. The steroid system has been extensively used as a privileged scaffold gifted with significantly diversified medicinal properties in the drug discovery and development process. Steroidal molecules are preferred for their rigidness and good ability to penetrate biological membranes. Slight alteration in the basic ring structure results in the formation of steroidal derivatives with a wide range of therapeutic activities. Steroids are not only active as such, conjugating them with various biologically active moieties results in increased lipophilicity, stability, and target specificity with decreased adverse effects. Thus, the steroid nucleus prominently behaves as a biological carrier for small molecules. The steroid bioconjugates offer several advantages such as synergistic activity with fewer side effects due to reduced dose and selective therapy. The steroidal bioconjugates have been widely explored for their usefulness against various disorders and have shown significant utility as anticancer, anti-inflammatory, anticoagulant, antimicrobial, insecticidal/pesticidal, antioxidant, and antiviral agents along with several other miscellaneous activities. This work provides a comprehensive review on the therapeutic progression of steroidal bioconjugates as medicinally active molecules. The review covers potential biological applications of steroidal bioconjugates and would benefit the wider scientific community in their drug discovery endeavors.

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Discovery of Steroidal Lactam Conjugates of POPAM-NH ₂ With Potent Anticancer Activity

Cited by 6 publications

References 42 publications

Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

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Discovery of Steroidal Lactam Conjugates of POPAM-NH 2 With Potent Anticancer Activity

Cited by 6 publications

References 42 publications

Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma

Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay

A Comprehensive Review on Steroidal Bioconjugates as Promising Leads in Drug Discovery

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Discovery of Steroidal Lactam Conjugates of POPAM-NH ₂ With Potent Anticancer Activity