[4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and ß-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

In Vitro Effect of 9,9'-Norharmane Dimer against Herpes Simplex Viruses.

Herpes simplex virus (HSV) infections are highly widespread among humans, producing symptoms ranging from ulcerative lesions to severe diseases such as blindness and life-threatening encephalitis. At present, there are no vaccines available, and some existing antiviral treatments can be ineffective or lead to adverse effects. As a result, there is a need for new anti-HSV drugs. In this report, the in vitro anti-HSV effect of 9,9'-norharmane dimer (nHo-dimer), which belongs to the ß-carboline (ßC) alkaloid family, was evaluated. The dimer exhibited no virucidal properties and did not impede either the attachment or penetration steps of viral particles. The antiviral effect was only exerted under the constant presence of the dimer in the incubation media, and the mechanism of action was found to involve later events of virus infection. Analysis of fluorescence lifetime imaging data showed that the nHo-dimer internalized well into the cells when present in the extracellular incubation medium, with a preferential accumulation into perinuclear organelles including mitochondria. After washing the host cells with fresh medium free of nHo-dimer, the signal decreased, suggesting the partial release of the compound from the cells. This agrees with the observation that the antiviral effect is solely manifested when the alkaloid is consistently present in the incubation media.

A ß-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer.

Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of ß-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.

Comparison of target agent treatment strategies for platinum-resistant recurrent ovarian cancer: A Bayesian network meta-analysis.

BACKGROUND: We aimed to compare 7 newer immunotherapies and targeted therapies for platinum-resistant relapsed ovarian cancer. METHODS: We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library electronic databases for phase III trials involving platinum-resistant recurrent ovarian cancer (PRrOC) patients treated with immunotherapy or targeted therapy in combination with chemotherapy. The quality of the included trials was assessed using the GRADE method. The primary outcome of comparison was progression-free survival, and secondary outcomes included overall survival and safety. RESULTS: This analysis included 7 randomized phase III controlled trials, encompassing 2485 PRrOC patients. Combining bevacizumab plus chemotherapy and lurbinectedin demonstrated statistically significant differences in progression-free survival compared to all other regimens of interest. However, no statistically significant differences were observed in the overall survival. Nivolumab and mirvetuximab exhibited fewer serious adverse events than the other regimens of interest. CONCLUSIONS: Our findings indicate that bevacizumab combined with chemotherapy and lurbinectedin monotherapy has significant efficacy in patients with PRrOC. For patients with PRrOC who have exhausted treatment options, nivolumab and mirvetuximab may be considered as alternatives because of their better safety profiles.

Synthesis and new DNA targeting activity of 6- and 7-tert-butylfascaplysins.

Fascaplysin is a red cytotoxic pigment with anticancer properties isolated from the marine sponge Fascaplysinopsis sp. Recently, structure-activity relationship analysis reported by our group suggested that selective cytotoxicity of fascaplysin derivatives towards tumor cells negatively correlates with their ability to intercalate into DNA. To validate this hypothesis, we synthesized 6- and 7-tert-butylfascaplysins which reveal mitigated DNA-intercalating properties. These derivatives were found to be strongly cytotoxic to drug-resistant human prostate cancer cells, albeit did not demonstrate improved selectivity towards cancer cells when compared to fascaplysin. At the same time, kinome analysis suggested an activation of CHK1/ATR axis in cancer cells shortly after the drug exposure. Further experiments revealed induction of replication stress that is eventually converted to the toxic DNA double-strand breaks, resulting in caspase-independent apoptosis-like cell death. Our observations highlight new DNA-targeting effect of some fascaplysin derivatives and indicate more complex structure-activity relationships within the fascaplysin family, suggesting that cytotoxicity and selectivity of these alkaloids are influenced by multiple factors. Furthermore, combination with clinically-approved inhibitors of ATR/CHK1 as well as testing in tumors particularly sensitive to the DNA damage should be considered in further studies.

Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1.

The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Pharmacokinetic considerations for drugs that treat diarrhea-predominant irritable bowel syndrome: what's new?

INTRODUCTION: Irritable bowel syndrome (IBS), which presents a significant healthcare and socioeconomic burden, is one of the main issues in the field of therapy. Hence, it is imperative to tackle this matter by evaluating the safety and efficacy of the available treatments and determining the ideal approach for each patient. AREAS COVERED: We reviewed the pharmacokinetics and safety of pharmacologic interventions administered in diarrhea-predominant IBS (IBS-D) patients. PubMed, Google Scholar and the USFDA databases were searched up to November 2023 to include all updated information on eluxadoline, alosetron, and rifaximin. EXPERT OPINION: The most effective way to treat IBS-D is to focus on managing the most common symptoms. However, healthcare providers face a challenge when it comes to identifying the right treatment for each patient, and the root cause of this is the diversity of IBS-D population. Studies have shown that there are differences in how men and women metabolize drugs, which may lead to gender-specific adverse reactions. Women tend to have higher drug concentrations in their bloodstream and take longer to eliminate them. Therefore, healthcare providers may need to reduce the dosage for female patients. Integrating IBS care into sustainable development efforts can indirectly contribute to achieving SDGs and promote health and well-being for all.

Anticancer mechanisms of ß-carbolines.

ß-Carboline nucleus is therapeutically valuable in medicinal chemistry for the treatment of varied number of diseases, most importantly cancer. The potent and wide-ranging activity of ß-carboline has established them as imperative pharmacological scaffolds especially in the cancer treatment. Numerous derivatives such as Tetrahydro ß-carbolines, metal complexed ß-carbolines, mono, di and tri substituted ß-carbolines have been reported to possess dynamic anticancer activity. These different substituted ß-carboline derivatives had shown different mechanism of action and plays important role in anticancer drug discovery and development. The review is an update of the chemistry of ß-carbolines, both synthetic and natural origin acting through various targets against cancerous cells. In addition to this, studies of multitarget molecules designed by coupling ß-carbolines along with other mechanisms for treatment of neoplasm are also summarized.

Recent Advances in the Synthesis of the Marine-Derived Alkaloid Fascaplysin and Its Metabolites Homofascaplysins A-C.

The fascaplysin and homofascaplysin class of marine natural products has a characteristic 12H-pyrido[1,2-a:3,4-b']diindole pentacyclic structure. Fascaplysin was isolated in 1988 from the marine sponge Fascaplysinopsis bergquist sp. The analogs of fascaplysin, such as homofascaplysins A, B, and C, were discovered late in the Fijian sponge F. reticulate, and also have potent antimicrobial activity and strong cytotoxicity against L-1210 mouse leukemia. In this review, the total synthesis of fascaplysin and its analogs, such as homofascaplysins A, B, and C, will be reviewed, which will offer useful information for medicinal chemistry researchers who are interested in the exploration of marine alkaloids.

Formation, Identification, and Occurrence of the Furan-Containing ß-Carboline Flazin Derived from l-Tryptophan and Carbohydrates.

ß-Carbolines (ßCs) are bioactive indole alkaloids found in foods and in vivo. This work describes the identification, formation, and occurrence in foods of the ßC with a furan moiety flazin (1-[5-(hydroxymethyl)furan-2-yl]-9H-pyrido[3,4-b]indole-3-carboxylic acid). Flazin was formed by the reaction of l-tryptophan with 3-deoxyglucosone but not with 5-hydroxymethylfurfural. Its formation was favored in acidic conditions and heating (70-110 °C). The proposed mechanism of formation occurs through the formation of intermediates 3,4-dihydro-ß-carboline-3-carboxylic acid (imines), followed by the oxidation to C═O in the carbohydrate chain and aromatization to ßC ring with subsequent dehydration steps and cyclization to afford the furan moiety. Flazin is generated in the reactions of tryptophan with carbohydrates. Its formation from fructose was higher than from glucose, whereas sucrose gave flazin under acidic conditions and heating owing to hydrolysis. Flazin was identified in foods by HPLC-MS, and its content was determined by HPLC-fluorescence. It occurred in numerous processed foods, such as tomato products, including crushed tomato puree, fried tomato, ketchup, tomato juices, and jams, but also in soy sauce, beer, balsamic vinegar, fruit juices, dried fruits, fried onions, and honey. Their concentrations ranged from not detected to 22.3 µg/mL, with the highest mean levels found in tomato concentrate (13.9 µg/g) and soy sauce (9.4 µg/mL). Flazin was formed during the heating process, as shown in fresh tomato juice and crushed tomatoes. These results indicate that flazin is widely present in foods and is daily uptaken in the diet.

Considerations for selecting second-line treatment in patients with progressive small cell lung cancer and the use of Lurbinectedin in this setting.

Small cell lung cancer (SCLC) is characterized by high initial responses to platinum-based chemotherapy plus immune checkpoint inhibitors; however, most patients quickly relapse and require subsequent treatment. Second-line treatment options in SCLC remain limited, and treatment algorithms are not completely consistent across the available guidelines in this setting. This review highlights key considerations regarding selection of second-line treatment for patients with relapsed SCLC. In particular, the role of lurbinectedin, which was first approved in 2020, representing the first significant addition to treatment algorithms in this setting for decades, is summarized. Future directions, including the identification of SCLC subtypes and the need for predictive biomarkers to guide patient selection and targeted therapy, are also discussed.

1-Ethoxycarbonyl-beta-carboline inhibits the M2 polarization of tumor-associated macrophages: A study based on network pharmacology and molecular docking analyses.

AIM: Through network pharmacology, molecular docking, molecular dynamics in combination with experimentation, we explored the mechanism whereby 1-ethoxycarbonyl-beta-carboline (EBC) regulates the M2 polarization of tumor-associated macrophages. METHODS: Network pharmacology was adopted for analyzing the targets and signaling pathways related to the M2 polarization of EBC-macrophages, small molecular-protein docking was employed to analyze the possibility of EBC bonding to related protein, and molecular dynamics was introduced to analyze the binding energy between EBC and HDAC2. The M2 polarization of RAW264.7 macrophages was triggered in vitro by IL-4. After EBC intervention, the expressions of M1/M2 polarization-related cytokines were detected, and the mechanism of EBC action was explored in HDAC2-knockout RAW264.7 macrophages. A tumor-bearing mouse model was established in vitro to find the impact of EBC on tumor-associated M2 macrophages. RESULTS: As revealed by the network pharmacology, molecular docking and molecular dynamics analyses, EBC was associated with 51 proteins, including HDAC2, NF-κB and HDAC4. Molecular docking and dynamics analyses suggested that HDAC2 was the main target of EBC. In vitro experiments discovered that EBC could hinder the M2 polarization of RAW264.7 macrophages, which exerted insignificant effect on the M1-associated cytokines, but could lower the levels of M2-associated cytokines. After knocking out HDAC2, EBC could not further inhibit the M2 polarization of macrophages. At the mouse level, EBC could hinder the tumor growth and the tissue levels of M2 macrophages, whose effect was associated with HDAC2. CONCLUSION: Our study combining multiple methods finds that EBC inhibits the HDAC2-mediated M2 polarization of macrophages, thereby playing an anti-tumor role.

Single-dose Tadalafil Reduces Opening Urethral Pressure: A Randomized, Double-blind, Placebo-controlled, Crossover Trial in Healthy Women.

INTRODUCTION AND HYPOTHESIS: Phosphodiesterase enzymes are widely distributed in female urogenital tissues. Yet, the understanding of their physiological roles and the impact of phosphodiesterase inhibitors on lower urinary tract symptoms in women remains limited. Current hypotheses are conflicting: one suggests that vasodilation might expand the periurethral vascular plexus, leading to increased urethral pressure, whereas the other proposes a relaxation of urethral musculature, resulting in decreased pressure. To further clarify this, we investigated the effect of tadalafil on the opening urethral pressure and voiding function in healthy women. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial involving 24 healthy women. Participants were randomly assigned to receive a single dose of tadalafil (40 mg) or placebo during their initial visit and then switched to the alternative treatment during their second visit. Opening urethral pressure was measured with urethral pressure reflectometry during both resting and squeezing conditions of the pelvic floor. Subsequently, voiding parameters were recorded. RESULTS: Compared with placebo, a single dose of tadalafil significantly reduced opening urethral pressure during both resting (-6.8 cmH20; 95% confidence interval [CI], -11.8 to -1.9; p = 0.009) and squeezing conditions (-8.8 cmH20; 95% CI, -14.6 to -3.1; p = 0.005). Voiding parameters did not show significant differences (average flow rate: -0.8 ml/s [95% CI, -2.0 to 0.4; p = 0.2]; maximum flow rate: -1.7 ml/s [95% CI, -4.8 to 1.5; p = 0.3]). CONCLUSIONS: A single dose of 40 mg tadalafil moderately reduced urethral pressure in healthy women, without affecting voiding parameters. The clinical implications of this are yet to be determined.

Rational molecular design converting fascaplysin derivatives to potent broad-spectrum inhibitors against bacterial pathogens via targeting FtsZ.

The filamentous temperature-sensitive mutant Z protein (FtsZ), a key player in bacterial cell division machinery, emerges as an attractive target to tackle the plight posed by the ever growing antibiotic resistance over the world. Therefore in this regard, agents with scaffold diversities and broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens are highly needed. In this study, a new class of marine-derived fascaplysin derivatives has been designed and synthesized by Suzuki-Miyaura cross-coupling. Some compounds exhibited potent bactericidal activities against a panel of Gram-positive (MIC = 0.024-6.25 µg/mL) and Gram-negative (MIC = 1.56-12.5 µg/mL) bacteria including methicillin-resistant S. aureus (MRSA). They exerted their effects by dual action mechanism via disrupting the integrity of the bacterial cell membrane and targeting FtsZ protein. These compounds stimulated polymerization of FtsZ monomers and bundling of the polymers, and stabilized the resulting polymer network, thus leading to the dysfunction of FtsZ in cell division. In addition, these agents showed negligible hemolytic activity and low cytotoxicity to mammalian cells. The studies on docking and molecular dynamics simulations suggest that these inhibitors bind to the hydrophilic inter-domain cleft of FtsZ protein and the insights obtained in this study would facilitate the development of potential drugs with broad-spectrum bioactivities.

Synthesis and biological evaluation of 1-phenyl-tetrahydro-ß-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents.

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-ß-carboline (THßC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC50 values of 15.47 ± 1.31 and 19.31 ± 2.14 µM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC50 values below 10 µM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents.

Characterization of alkaloids and phenolics in Nitraria roborowskii Kom. fruit by UHPLC-triple-TOF-MS/MS and its sucrase and maltase inhibitory effects.

Nitraria roborowskii Kom (NRK), with high economic and ecological value, is mainly distributed in the Qaidam Basin, China. However, research on its chemical components and bioactivities is still rare. In this study, its chemical constituents (52) including 10 ß-carboline alkaloids, nine cyclic peptides, three indole alkaloids, five pyrrole alkaloids, eight phenolic acids and 17 flavonoids were identified tentatively using UPLC-triple-TOF-MS/MS. Notablely, one new ß-carboline alkaloid and five new cyclic peptides were confirmed using MS/MS fragmentation pathways. In addition, experiments in vitro indicated that NRK-C had strong maltase and sucrase inhibitory activities (IC50 of 0.202 and 0.103 mg/mL, respectively). Polysaccharide tolerance experiments confirmed NRK-C (400 mg/kg) was associated with decreased postprandial blood glucose (PBG) in diabetic mice. These results suggested that NRK fruit might be used as a functional ingredient in food products.

The association of tadalafil exposure with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction.

BACKGROUND: Tadalafil is a long-acting phosphodiesterase-5 inhibitor (PDE-5i) indicated for erectile dysfunction (ED). HYPOTHESIS: Our hypothesis was that tadalafil will reduce the risk of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction, coronary revascularization, unstable angina, heart failure, stroke) and all-cause death in men with ED. METHODS: A retrospective observational cohort study was conducted in a large US commercial insurance claims database in men with a diagnosis of ED without prior MACE within 1 year. The exposed group (n = 8156) had ≥1 claim for tadalafil; the unexposed group (n = 21 012) had no claims for any PDE-5i. RESULTS: Primary outcome was MACE; secondary outcome was all-cause death. Groups were matched for cardiovascular risk factors, including preventive therapy. Over a mean follow-up of 37 months for the exposed group and 29 months for the unexposed group, adjusted rates of MACE were 19% lower in men exposed to tadalafil versus those unexposed to any PDE-5i (hazard ratio [HR] = 0.81; 95% confidence intervals [CI] = 0.70-0.94; p = .007). Tadalafil exposure was associated with lower adjusted rates of coronary revascularization (HR = 0.69; 95% CI = 0.52-0.90; p = .006); unstable angina (HR = 0.55; 95% CI = 0.37-0.81; p = .003); and cardiovascular-related mortality (HR = 0.45; CI = 0.22-0.93; p = .032). Overall mortality rate was 44% lower in men exposed to tadalafil (HR = 0.56; CI = 0.43-0.74; p < .001). Men in the highest quartile of tadalafil exposure had the lowest rates of MACE (HR: 0.40; 95% CI: 0.28-0.58; p < .001) compared to lowest exposure quartile. CONCLUSION: In men with ED, exposure to tadalafil was associated with significant and clinically meaningful lower rates of MACE and overall mortality.

Re-exploration of tetrahydro-ß-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities.

Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro-ß-carboline (THßC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC50, 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner. In vitro, 11d induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of H2O2-induced oxidative stress.

3-Amide-ß-carbolines block the cell cycle by targeting CDK2 and DNA in tumor cells potentially as anti-mitotic agents.

ß-Carboline alkaloids are natural and synthetic products with outstanding antitumor activity. C3 substituted and dimerized ß-carbolines exert excellent antitumor activity. In the present research, 37 ß-carboline derivatives were synthesized and characterized. Their cytotoxicity, cell cycle, apoptosis, and CDK2- and DNA-binding affinity were evaluated. ß-Carboline monomer M3 and dimer D4 showed selective activity and higher cytotoxicity in tumor cells than in normal cells. Structure-activity relationships (SAR) indicated that the amide group at C3 enhanced the antitumor activity. M3 blocked the A549 (IC50 = 1.44 ± 1.10 µM) cell cycle in the S phase and inhibited A549 cell migration, while D4 blocked the HepG2 (IC50 = 2.84 ± 0.73 µM) cell cycle in the G0/G1 phase, both of which ultimately induced apoptosis. Furthermore, associations of M3 and D4 with CDK2 and DNA were proven by network pharmacology analysis, molecular docking, and western blotting. The expression level of CDK2 was downregulated in M3-treated A549 cells and D4-treated HepG2 cells. Moreover, M3 and D4 interact with DNA and CDK2 at sub-micromolar concentrations in endothermic interactions caused by entropy-driven adsorption processes, which means that the favorable entropy change (ΔS > 0) overcomes the unfavorable enthalpy change (ΔH > 0) and drives the spontaneous reaction (ΔG < 0). Overall, these results clarified the antitumor mechanisms of M3 and D4 through disrupting the cell cycle by binding DNA and CDK2, which demonstrated the potential of M3 and D4 as novel antiproliferative drugs targeting mitosis.