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PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC50 value of 1.56 µM and 1.22 µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.

The design, synthesis and biological evaluation of 4-substituted 5-methyl-furo[2,3-d]pyrimidines is described. The Ullmann coupling of 5-methyl-furo[2,3-d]pyrimidine with aryl iodides was successfully optimized to synthesize these analogs. Compounds 6-10 showed single-digit nanomolar inhibition of EGFR kinase. Compounds 1 and 6-10 inhibited VEGFR-2 kinase better than or equal to sunitinib. Compounds 1 and 3-10 were more potent inhibitors of PDGFR-β kinase than sunitinib. In addition, compounds 4-11 had higher potency in the CAM angiogenesis assay than sunitinib. Compound 1 showed in vivo efficacy in an A498 renal xenograft model in mice. Multiple RTK and tubulin inhibitory attributes of 1, 4, 6 and 8 indicates that these compounds may be valuable preclinical single agents targeting multiple intracellular targets.

Graphical abstract, NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1β IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.

Although dual inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) enzymes is highly effective than targeting COX or LOX alone, there are only a few reports of examining such compounds in case of colorectal cancers (CRC). In the present work we report that the novel di-tert-butyl phenol-based dual inhibitors DTPSAL, DTPBHZ, DTPINH, and DTPNHZ exhibit significant cytotoxicity against human CRC cell lines. Molecular docking studies revealed a good fit of these compounds in the COX-2 and 5-LOX protein cavities. The inhibitors show significant inhibition of COX-2 and 5-LOX activities and are effective against a panel of human colon cancer cell lines including HCA-7, HT-29, SW480 and intestinal Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressing colon cancer cells, through inhibition of the Hyaluronan/CD44v6 cell survival pathway. Western blot analysis and qRT-PCR analyses indicated that the di-tert-butyl phenol-based dual inhibitors reduce the expression of COX-2, 5-LOX, and CD44v6 in human colon cancer HCA-7 cells, while the combination of CD44v6shRNA and DTPSAL has an additional inhibitory effect on CD44v6 mRNA expression. The synergistic inhibitory effect of Celecoxib and Licofelone on CD44v6 mRNA expression suggests that the present dual inhibitors down-regulate cyclooxygenase and lipoxygenase enzymes through CD44v6. The compounds also exhibited enhanced antiproliferative potency compared to standard dual COX/LOX inhibitor, viz. Licofelone. Importantly, the HA/CD44v6 antagonist CD44v6shRNA in combination with synthetic compounds had a sensitizing effect on the cancer cells which enhanced their antiproliferative potency, a finding which is crucial for the anti-proliferative potency of the novel synthetic di-tert-butyl phenol based dual COX-LOX inhibitors in colon cancer cells.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy. AG 3 was found to be the most active compound.

3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.

A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.

The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.

Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.

We have recently identified BMS-345541 (1) as a highly selective and potent inhibitor of IKK-2 (IC50 = 0.30 μM), which however was considerably less potent against IKK-1 (IC50 = 4.0 μM). In order to further explore the SAR around the imidazoquinoxaline tricyclic structure of 1, we prepared a series of tetracyclic analogues (7, 13, and 18). The synthesis and biological activities of these potent IKK inhibitors are described.

A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.

Andrographolide 1, the cytotoxic agent of the plant Andrographis paniculata was subjected to semi-synthetic studies leading to the preparation of a number of potent and novel analogues. Of the analogues synthesized, while 8,17-epoxy andrographolide 6 retained the cytotoxic activity of 1, ester derivatives of 6 exhibited considerable improvement in activity. Lower activity was observed when the epoxy moiety in the triacetate 9, derived from 6 was modified. Synthesis and structure-activity relationships are discussed.

The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.

The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.

A synthesis of the C-2-acetoxy-C-4-benzoate paclitaxel 2 is described. This analog has the substituents at C-2 and C-4 transposed. The key steps in the synthesis include the sequential use of Red-Al as reducing agent for the regioselective reduction of the C-2 benzoate and the C-4 acetoxy within the baccatin core. Iso-paclitaxel 2 was considerably less potent than paclitaxel in tubulin polymerization and in vitro cytotoxicity assays.

An efficient syntheses of the 3′-N isomeric paclitaxel analogs, 4 and 5, are described. A highly diastereoselective Sharpless asymmetric dihydroxylation reaction is utilized to establish the required (2′R,3′S) stereochemistry on the C-13 side chain. Both of the 3′-N modified analogs 4 and 5 were found to be cytotoxic in vitro. Analog 4 also displayed comparable in vivo activity to that of paclitaxel in the ip M-109 tumor model.

The synthesis, pharmacokinetic properties, and antitumor evaluation of novel paclitaxel phosphonooxymethyl ether derivatives 8–11 and salts thereof is described. These compounds exhibit improved water solubility as compared to paclitaxel (1) and upon incubation with plasma and alkaline phosphatase they readily release parent drug. The in vivo antitumor evaluation of compounds 8–11 established them as suitable pro-drugs of paclitaxel.

A large number of C-4 paclitaxel analogs have been prepared in the course of our systematic C-4 modification. These include C-4 esters, carbonates, carbamates as well as a C-4 deacetyl derivative. All of these analogs were evaluated in a tubulin polymerization assay as well as in a cytotoxicity assay against a human colon cancer cell line. The potent analogs emerging from these in vitro assays were further evaluated in vivo. With the exception of paclitaxel side chain bearing C-4 carbamates and C-4 aromatic esters, most of the C-4 aliphatic esters and carbonates were found to possess comparable or superior activity to paclitaxel in vitro. Several C-4 aliphatic esters and carbonates also exhibited in vivo activities against i.p. implanted murine M-109 lung carcinoma.

Three new phosphate derivatives of paclitaxel-2′-ethylcarbonate 4a, 4b, and 4c, have been synthesized and evaluated for in vivo antitumor activity. All were soluble in water and two derivatives 4a and 4b were found to exhibit in vivo antitumor activity, comparable to paclitaxel in the M109 murine tumor model.

The thiol activation and aromatization of bicyclo[7.1.0]enediynes was found to be dependent of the nature of the propargyl substituent. These effects are correlated to antitumor activity.

Etoposide Phosphate (BMY-40481) is synthesized semisynthetically from the clinically approved anticancer parent drug, etoposide (VP-16-213), and also from natural (−)-epipodophyllotoxin. Etoposide phosphate functions as a clinically active, water soluble prodrug of etoposide. The NDA for etoposide phosphate was filed in June, 1994.

A series of taxol derivatives, modified at C-7, is described. This includes sulfonate, silylether, ester, carbonate, carbamate, fluoro, dehydro and deoxy derivatives. Biological evaluation shows that these modifications do not usually significantly compromise activity. However, none of the C-7 analogs prepared thus far have been shown to be better than taxol in both in vitro and in vivo assays.

A new class of guanidino prodrug is efficiently synthesized from an amine and an appropriate N,N′-bis(acyloxymethoxycarbonyl)-S-methylisothiourea. The N,N′-bis(acyloxymethoxycarbonyl)-S-methylisothiourea is readily prepared from S-methylisothiourea and the corresponding acyloxymethyl carbonochloridate in good yield. The N,N′-bis(acyloxymethyl carbamate) derivatives of the highly basic guanidino group serve as lipophilic, uncharged, esterase-activatable prodrugs of simple guanidine containing molecules.

A number of 2′-oxycarbonylpaclitaxels (paclitaxel-2′-carbonates) 3 have been prepared and evaluated for their cytotoxicity and in vivo antitumor activity. Most of these paclitaxel-2′-carbonates were found to exhibit in vivo antitumor activity in the i.p. M109 murine tumor model system, comparable to that of the parent drug.

Novel analogues of TAXOL ® with an additional hydroxyl group at the C-14 position were synthesized and evaluated as antitumor agents.

Red-Al was used to selectively remove the C 2 benzoate of 7,13-bisTES baccatin ( 8 ). Derivatization of the resulting C 2 hydroxy compound provided the corresponding p-nitrophenyl carbamate, the p-methoxy and p-nitrobenzoates, and cyclohexyl ester. Attachment of the taxol side chain to the above four analogs via lactam ( 15 ) followed by desilylation provided five analogs of taxol modified at the C 2 position, including a C 1,2 cyclic carbonate. These five analogs were less potent than taxol in a tubulin polymerization assay and a cytotoxicity assay against human colon cancer cell line.

Core-modified sordaricin derivatives were prepared via biotransformation followed by chemical modification and tested for antifungal activity. The antifungal activity proved to be very sensitive to modifications in the sterics and/or lipophilicity of the diterpene skeleton. Introduction of polar groups such as hydroxyl in the diterpene core results in loss of potency while small and lipophilic groups such as fluorine and the 7,8-olefin are well tolerated.

Analogues of taxol with a modified phenylisoserine side chains were synthesized and evaluated as potential cytotoxic agents.

The E-ring 3′,4′,5′-trihydroxy etoposide analog 3 of the clinical antitumor agent etoposide 1 was synthesized from the corresponding etoposide ortho-quinone 2 . This analog is twice as potent as etoposide in its ability to elicit topoisomerase II mediated DNA double strand breaks. However, our in vitro cytotoxicity assay, using human colon tumor cells grown in culture, and our in vivo P388 murine leukemia screen reveal considerable loss of potency and/or activity vis-a-vis etoposide.

Synthesis and biological evaluation of novel taxol derivatives having a phosphonoxyphenylpropionate ester group at the 2′-position or at the 7-position of taxol are described. These were found to have much improved water solubility and both were found to generate taxol upon exposure to alkaline phosphatase. A particular derivative, 7-phosphonoxyphenylpropionate of taxol 3b exhibited antitumor activity comparable to that of taxol against the ip/ip M109 murine tumor model.

The simple enediyne core molecule 1 is shown to cause protein damage to several cellular protein isolates in vitro. The aromatization of 1 to generate a benzene diradical under simulated physiological conditions is also described.

Synthesis and in vivo antitmor evaluation of water soluble 2′- and 7-taxol phosphates is reported. These derivatives were found to be poor prodrugs of taxol based on their marginal in vivo antitumor activity against ip,ip M109 murine tumor model and taxol release studies in vitro .

New analogues of paclitaxel (1a, active constituent of Taxol®) were synthesized containing an epoxide at the C-10 position. The introduction of the epoxide was carried out by selective removal of the C10-acetate followed by protection of the C2′- and C7-hydroxyl groups. After oxidation to yield a ketone at the C10-position, this intermediate was reacted with dimethylsulfonium ylide. Deprotection and further manipulations provide the C10-spiro epoxide of paclitaxel (1b) and the corresponding C7-MOM ether (1c).

The E-ring 4′-deshydroxy-4′-methyl analogs of the clinical antitumor agents etoposide and teniposide were synthesized from the corresponding 4′-triflates. These compounds display significant antitumor activity against murine P388 leukemia in vivo but are only 1/5 as cytotoxic against a human colon tumor cell line (HCT-116) grown in culture. These analogs also show inferior activity vis-a-vis etoposide and teniposide when evaluated for their ability to inhibit purified human topoisomerase II.