Prostate cancer (PCa) patients commonly experience clinical depression. Recent reports indicated that monoamine oxidase-A (MAO-A) levels elevate in PCa, and antidepressant MAO-Is show anti-PCa properties. In this work, we aimed to find potential drugs for PCa patients suffering from depression by establishing novel anti-PCa reversible monoamine oxidase-A inhibitors (MAO-AIs/RIMA); with an endeavor to understand their mechanism of action. In this investigation, twenty synthesized flavonoid derivatives, defined as KKR compounds were screened for their inhibitory potentials against human MAO-A and MAO-B isozymes. Meanwhile, the cytotoxic and antiproliferative effects were determined in three human PCa cell lines. MAO-A-kinetics, molecular docking, SAR, cell morphology, and cell migration were investigated for the most potent compounds. The screened KKRs inhibited MAO-A more potently than MAO-B, and non-toxically inhibited LNCaP cell proliferation more than the DU145 and PC3 cell lines, respectively. The results showed that the three top MAO-AI KKRs compounds (KKR11, KKR20, and KKR7 (IC₅₀s 0.02–16 μM) overlapped with the top six antiproliferative KKRs against LNCaP (IC₅₀s ~9.4 μM). While KKR21 (MAO-AI) and KKR2A (MAO-I) were ineffective against the PCa cells. Furthermore, KKR21 and KKR11 inhibited MAO-A competitively (K_is ≤ 7.4 nM). Molecular docking of the two compounds predicted shared hydrophobic and distinctive hydrophilic interactions—between the KKR molecule and MAO-A amino acid residues—to be responsible for their reversibility. The combined results and SAR observations indicated that the presence of specific active groups—such as chlorine and hydroxyl groups—are essential in certain MAO-AIs with anti-PCa effects. Additionally, MAO-A inhibition was found to be associated more with anti-PCa property than MAO-B. Distinctively, KKR11 [(E)-3-(3,4-dichlorophenyl)-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one] exhibited anti-metastatic effects on the DU145 cell line. The chlorine substitution groups might play vital roles in the KKR11 multiple actions. The obtained results indicated that the flavonoid derivative KKR11 could present a novel candidate for PCa patients with depression, through safe non-selective potent inhibition of MAOs.

Aim: : The aim of our research work is the synthesis of tetrahydroisoquinoline derivatives as anti-Angiogenesis and anti-cancer agents. Background: : Cancer is the second leading cause of deaths in United States. The current recovery rate from the advanced treatment for the cancer is unacceptably low. Therefore, identification of novel, potent and less toxic anticancer agents remains a top priority. Objective: To 1) evaluate anti-angiogenesis, anticancer activities of THIQs on different colorectal cancer cell lines (CRC) viz., Colo320, DLD-1, HCT116, SNU-C1, SW480 and GSK3b in pre-treated viability HCT116. 2) Undertake molecular docking studies of THIQs. Methods: Twenty synthesized THIQs were screened in the Eli Lilly’s Open Innovation Drug Discovery Program and selected twelve compounds for in vitro primary screening in the KRas (Kirsten rat sarcoma)-Wnt SL (Synthetic Lethal) in the basal viability of different colon cancer cell lines. Docking studies of the active THIQs were also performed in our laboratory, targeting the active sites of KRas and VEGF receptors. Results: Compound GM-3-18 was found to possess significant activities for KRas inhibition, with IC50 values in the range of 0.9 μM to 10.7 μM, for all colon cancer cell lines. Compound GM-3-121 showed potent anti-angiogenesis activity with IC50 = 1.72 μM. Molecular docking studies showed that the carbonyl oxygen atoms of GM-3-18 and GM-3-121 showed hydrogen bonding interactions with the hydrogen of - OH groups of THR 74 (A). Conclusion: The results indicated that all the compounds showed moderate to high activity for KRas inhibition. The THIQs bearing the chloro group at the 4-position of the phenyl ring (GM-3-18) exhibited significant KRas inhibition against all colon cancer cell lines.

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The absence of chemotherapeutic target hormone receptors in breast cancer is descriptive of the commonly known triple-negative breast cancer (TNBC) subtype. TNBC remains one of the most aggressive invasive breast cancers, with the highest mortality rates in African American women. Therefore, new drug therapies are continually being explored. Microtubule-targeting agents such as paclitaxel (Taxol) interfere with microtubules dynamics, induce mitotic arrest, and remain a first-in-class adjunct drug to treat TNBC. Recently, we synthesized a series of small molecules of substituted tetrahydroisoquinolines (THIQs). The lead compound of this series, with the most potent cytostatic effect, was identified as 4-Ethyl-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl) benzamide (GM-4-53). In our previous work, GM-4-53 was similar to paclitaxel in its capacity to completely abrogate cell cycle in MDA-MB-231 TNBC cells, with the former not impairing tubulin depolymerization. Given that GM-4-53 is a cytostatic agent, and little is known about its mechanism of action, here, we elucidate differences and similarities to paclitaxel by evaluating whole-transcriptome microarray data in MDA-MB-231 cells. The data obtained show that both drugs were cytostatic at non-toxic concentrations and caused deformed morphological cytoskeletal enlargement in 2D cultures. In 3D cultures, the data show greater core penetration, observed by GM-4-53, than paclitaxel. In concentrations where the drugs entirely blocked the cell cycle, the transcriptome profile of the 48,226 genes analyzed (selection criteria: (p-value, FDR p-value < 0.05, fold change −2< and >2)), paclitaxel evoked 153 differentially expressed genes (DEGs), GM-4-53 evoked 243 DEGs, and, of these changes, 52/153 paclitaxel DEGs were also observed by GM-4-53, constituting a 34% overlap. The 52 DEGS analysis by String database indicates that these changes involve transcripts that influence microtubule spindle formation, chromosome segregation, mitosis/cell cycle, and transforming growth factor-β (TGF-β) signaling. Of interest, both drugs effectively downregulated “inhibitor of DNA binding, dominant negative helix-loop-helix” (ID) transcripts; ID1, ID3 and ID4, and amphiregulin (AREG) and epiregulin (EREG) transcripts, which play a formidable role in cell division. Given the efficient solubility of GM-4-53, its low molecular weight (MW; 296), and capacity to penetrate a small solid tumor mass and effectively block the cell cycle, this drug may have future therapeutic value in treating TNBC or other cancers. Future studies will be required to evaluate this drug in preclinical models.

According to World Health Organization, breast cancer is second leading cause of mortality among women, accounting for 12% of all new annual cancer cases worldwide. In 2021, the American Cancer Society (ACS) reported that there will be 281,550 new cases of breast cancer in U.S. and about 43,600 women will be expected to die from the disease. Unfortunately, the recovery rate from advanced breast cancer by current available drug treatment is unacceptably low. Hence, there is an urgent need to develop more effective and less toxic small drug molecules with a unique mechanism of action. Chromones are benzannulated oxygen containing heterocyclic compounds that are widely distributed in nature and have a gamma-pyrone ring. Natural and synthetic molecules having chromone scaffold displayed interesting pharmacological activities such as anti-cancer, anti-HIV, antiviral and anti-inflammatory activities with low toxicity. In continuation of our current research work, we report the synthesis of substituted tetrahydroisoquinoline chromone carboxamides. Modifications of the chromone scaffold at pyrone ring by attaching substituted tetrahdyrosioquinolines were carried out to prepare compounds with a potential of acting as anti-breast cancer agents. The starting material, substituted chromone-2-carbonyl chloride was obtained by the acylation reaction of corresponding carboxylic acids using phosphorous pentachloride in dry cyclohexane. An equimolar amount of acyl chloride was slowly added to a stirred solution of corresponding substituted N-aminoisoquinoline in dry THF, in the presence of triethyl amine and refluxed at 70 degrees C that led to the formation of the ylides. The ylides were reduced using sodium borohydride to yield the desired substituted tetrahydroisoquinoline chromone-2-carboxamides in moderate to good yields. The synthesized compounds were characterized by NMR, IR, and elemental analysis. These compounds were evaluated for their cytotoxic effects on MBA-MB-231 ER-ve breast cancer cell lines using a Synergy HTX multi-mode reader (Bio-Tek, Winooski, VT, USA) with excitation/emission wavelength settings at 550/580. Compound N-(3,4-dihydroisoquinolin-2-(1H0-yl)-6-methyl-4-oxo-4H-1-benzopyran-2-carboxmaide showed the most potent cytotoxicity with an IC₅₀ value 0.82 microgram/mL on MDA-MB-231 cell line. This research was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under the Award Number U54 MD007582. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Citation Format: Kinfe Ken Redda, Madhavi Gangapuram, Elizabeth Mazzio, Ramesh Badisa, Suresh Eyunni, Karam F. A. Soliman. Synthesis of substituted tetrahydroisoquinoline chromone-2-carboxamidesas anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1889.