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Cyclopentanoids and their derivatives are interesting targets in synthetic organic chemistry due to their extensive applications in various branches of chemical sciences like pharmaceuticals, natural and non-natural products. In view of these applications, several synthetic strategies have been developed in the past three to four decades. In this article, we describe our work towards the synthesis of cyclopentanoids and their heteroanalogs involving diverse synthetic strategies during the past two decades. Among these, photo-thermal olefin metathesis, ring-closing metathesis, ring-rearrangement metathesis, cyclopentane annulation, [2+2+2] cycloaddition and Diels–Alder reactions have been used to assemble cyclopentane rings of diverse architecture. 1 Introduction 2 Synthesis of Spiro[4.4]nonane (A1) Derivatives 3 Synthesis of Octahydropentalene (A2) Derivatives 4 Synthesis of Linear Triquinanes (A3) 5 Synthesis Spiro Triquinanes (A4) 6 Synthesis of Angular Triquinane (A5) Systems 7 Synthesis of Hexahydro-2′H-spiro[cyclopentane-1,1′-pentalene] (A6) Ring System 8 Synthesis of Dispiro[4.1.47.25]tridecane (A7) Ring System 9 Synthesis of Hexahydro-1H-3a,7a-propanoindene Ring System10 Synthesis of Linear Tetraquinanes (A11 and A12)11 Synthesis of Tetrahydro-1′H,3′H-dispiro[cyclopentane-1,2′-pentalene-5′,1′′-cyclopentane] (A13) Ring System12 Synthesis of Decahydro-1H,8H-dicyclopenta[a,h]pentalene (A14) Ring System13 Synthesis of Dodecahydro-1H-dicyclopenta[a,d]pentalene (A15) Ring System14 Synthesis of Octahydro-1′H-spiro[cyclopentane-1,2′-cyclopenta[c]pentalene] (A16) Ring System15 Synthesis of Decahydrospiro[cyclopentane-1,7′-cyclopenta-[a]pentalene] (A17) Ring System16 Synthesis of Compact Tetraquinane (A18)17 Synthesis of Higher Polyquinanes18 Conclusions19 Acronyms

Background: The synthesis of novel heterocyclic scaffolds with amide functionality is a key research area due to their plethora of medicinal applications. The present study aims to explore the synthesis of new cinnamido linked quinazolinone congeners and their potential as anticancer agents. Methods: Cytotoxicity evaluation, Cell cycle analysis, JC-1 staining, ROS, Annexin V assays, AO/EB, DAPI nuclear staining, Colony-forming assay and Western blot analysis. Results: Among the synthesized compounds, 5eb and 5fc have shown promising cytotoxic activity with an IC50 value of 3.89±1.01µM and 4.05±0.62µM against HeLa cell lines. The flow-cytometry analysis demonstrated that the compound 5eb arrested the sub-G1 phase of the cell cycle and induced apoptosis. Furthermore, the compound 5eb triggered the collapse of mitochondrial membrane potential (ΔΨm), which was assessed by JC-1 staining and also induced the generation of Reactive Oxygen Species. An increase in the expression of proapoptotic proteins such as Bax, p53, cleaved PARP and cleaved caspase-3 by 5eb confirmed the activation of the mitochondrial-dependent intrinsic apoptosis pathway. Conclusion: Our results suggest that compound 5eb and 5fc of cinnamido linked quinazolinone derivatives could serve as potential leads in the development of novel chemotherapeutic agents.

An efficient, metal-free approach to access pyrazolo-[1,5-c]quinazolines with 3-ylideneoxindoles and tosyldiazomethane (TsDAM) under mild aqueous reaction conditions has been developed and the solvent involvement in the present reaction has also been explored for the first time. This greener approach involves 1,3-dipolar cycloaddition, regioselective ring expansion, followed by the elimination of tosyl group with aqueous base in a single operation, and the product can be isolated in high purity without column chromatographic separation. The method is also compatible with a large variety of functional groups, providing good to excellent yields in water, thus resulting in a decrease of environmental impact in the pharmaceutical industry.

A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC50 values 13–45 nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05 nM and 13.84 nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.

An efficient molecular iodine-catalysed one-pot strategy has been accomplished for the construction of various fused heterocycles such as pyridoimidazoles, pyrrolo[1,2-a]quinoxalines and imidazobenzothiazoles under metal and oxidant free conditions. Gratifyingly, this method allows the sequential formation of C–N and C–C bonds with concomitant CO–C(alkyl) bond cleavage. The key features of this protocol are a broad substrate scope, operational simplicity, good to moderate yields and metal-free conditions, which make this protocol convenient for the generation of a library of fused polyheterocycles.

A series of new podophyllotoxin linked β-carboline congeners have been synthesized by coupling various substituted β-carboline acids with 4β-aminopodophyllotoxin. Evaluation of their anticancer activity against a panel of human cancer cell lines such as lung cancer (A549), prostate cancer (DU-145), MDA MB-231 (breast cancer), HT-29 (colon cancer) and HeLa (cervical cancer) suggested that 7i and 7j are the most cytotoxic compounds with IC50 values of 1.07 ± 0.07 μM and 1.14 ± 0.16 respectively against DU-145 cell line. Further, detailed biological studies such as cell cycle analysis, topoisomerase II inhibition, Comet assay, DNA binding studies and docking studies have revealed that these congeners are DNA interacting topoisomerase II inhibitors.

A facile and efficient metal-free, one-pot, three component synthetic protocol has been developed for the synthesis of medicinally important substituted imidazo[1,2-a]pyridines via the iodine-catalysed oxidative amination of benzylic C–H bonds of azaarenes with 2-aminoazines and condensation with isocyanides. The presented methodology offers the advantages of wide substrate scope, moderate reaction conditions, environment friendliness, clean and simple protocol with high atom economy apart from higher yields. The synthesized compounds were screened for their anti-cancer activity in selected human cancer cell lines. Compounds 4a, 4b, 4c, 4i, 7a, 7b and 7m have significant IC50 values ranging from 4.88 ± 0.28 to 14.55 ± 0.74 μM.

An efficient, operationally simple and one-pot multi-component approach has been developed for the construction of pyrazolyl-thiazoles using sulfamic acid (H2NSO3H) as a green catalyst in water. The notable features of this protocol include mild reaction conditions, enhanced selectivity with good yields and wide substrate scope, which makes it an attractive and useful process for the synthesis of biologically important newer pyrazolyl-thiazole compounds. A series of compounds (4a–z) were synthesized and also evaluated for their cytotoxic activity against three human cancer cell lines. Among them, 4b, 4c and 4e exhibited considerable cytotoxicity with an IC50 value of < 5 μM.

Neo-tanshinlactone (NTL) a natural product is known for its specificity and selectivity towards the breast cancer cells. By NTL D-ring modification approach, 13 new analogues were synthesized (1A-1M). Among them 1J showed the best anticancer activity in MCF-7 (ER+, PR+/-, HER2-), SKBR3 (ER-, PR-, HER2+) and MDA-MB-231 (ER-, PR-, HER2-) cells lines with IC50 value 11.98nM, 23.71nM, and 62.91nM respectively. 1J showed minor grove binding interaction with DNA at AT-rich region and induced DNA double strand breaks (DDSBs). This had triggered several key molecular events involving, activation of ATM, Chk2 and p53, reduction in mitochondrial potential (Δψm) leading to caspase-3 and PARP cleavage mediated apoptosis. These results along with other biochemical studies strongly suggest that novel NTL analogue 1J caused DNA cleavage mediated apoptosis in the breast cancer cells and this may serve as potential lead for future breast cancer treatment.

An operationally facile and high yielding one-pot, three-component protocol has been developed for the preparation of selectively trans-2,3-dihydrofuro[3,2-c]coumarins and trans-1,2-dihydrobenzo[h]furo[3,2-c]quinolinones. This protocol proceeds through a domino Knoevenagel condensation, a Michael addition followed by intramolecular SN2 cyclisation. All the synthesized compounds have been evaluated for their in vitro cytotoxic activity against selected human cancer cell lines. Interestingly, most of the compounds have exhibited considerable cytotoxicity with IC50 values

An efficient metal-free, one-pot protocol was developed for the synthesis of variety benzimidazole and quinazolinones in moderate to good yields. This protocol proceeds via oxidation of benzylamine, resulting in in-situ aldehyde formation followed by the condensation with o-phenylenediamine and o-aminobenzamide to the corresponding N-heterocycles using a mild oxidant phenyliodonium diacetate (PIDA). We describe a new strategy for C–N bond cleavage and formation in the absence of transition-metal reagent or ligand under environmentally benign reaction conditions.

A novel efficient one-pot regioselective ring-expansion reaction of isatins with in situ generated α-aryl/heteroaryldiazomethanes for the construction of viridicatin alkaloids has been described under metal-free conditions. The utility of this protocol is further demonstrated in the synthesis of naturally occurring viridicatin, viridicatol, and substituted 3- O-methyl viridicatin and their scale up.

A series of new β-carboline-dithiocarbamate derivatives bearing phenyl, dithiocarbamate and H/methyl substitutions at position-1, 3 and 9, respectively, were designed and synthesized. These derivatives 8a-l and 13a-l and their starting precursors (7 a-d and 12 a-d) have been evaluated for their in vitro cytotoxic activity on selected human cancer cell lines. Among the derivatives tested, 7 c, 12 c, 8 a, 8 d, 8 i, 8 j, 8 k, 8l and 13 d-l exhibited considerable cytotoxicity against most of the tested cancer cell lines (IC50

Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation of tetrahydro-β-carboline acids and dehydrogenation of tetrahydro-β-carbolines to access the corresponding aromatic β-carbolines. To the best of our knowledge this is the first synthesis of β-carbolines via a one-pot oxidative decarboxylation at ambient temperature. The utility of this protocol has been demonstrated in the synthesis of β-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12).

A facile method for the synthesis of a variety of β-carbolines and their natural products such as norharmane (2a), harmane (2b), eudistomins I, N, T, and U (6, 7, 9 and 10, respectively) has been successfully developed via a decorboxylative aromatization tool by employing N-chlorosuccinimide (NCS) as a mild and efficient reagent. Gratifyingly, this reagent system proceeds in a one-pot manner and converted all the tetrahydro-β-carboline acids into their corresponding decorboxylative aromatic products with good to excellent yields. Additionally, this system works well in the case of tetrahydro-β-carboline esters to produce their aromatic partners in high yields.

Chiral pyrrolidinyl-oxazole-carboxamides were synthesized and used as efficient new organocatalysts for the asymmetric Michael addition of ketones with nitroalkenes under solvent-free conditions. Gratifyingly, the corresponding Michael adducts were obtained in higher yields (up to 99%) and excellent stereoselectivities (up to >99/1 dr and 99% ee). Transition state models have been proposed to account for the high enantio- and diastereoselectivity of these Michael addition reactions and also the energetics have been investigated using density functional methods. These results support the preferential formation of syn-products by the approach of trans-β-nitrostyrene through the re-face of anti-enamine.

An efficient regio-selective aryl CH activation and tandem o-hydroxylation method for 2-arylbenzimidazoles has been developed by using a Pd(OAc)2/oxone/Cs2CO3 catalytic system. This reaction was successfully optimized by using various catalysts, oxidants, bases, and solvents to achieve the desired products in good yields. Further, preliminary mechanistic studies were conducted to examine the source of oxygen for this transformation. Gratifyingly, this catalytic system is also suitable for the introduction of various alkoxy groups, and delivered the products in good yields. The synthesized compounds were evaluated for their cytotoxic activity in selected human cancer cell lines. Some of the representative compounds (1 f, 2 f, 3 f and 4 f) have significant IC50 values ranging from 1–10 μM. Structure-activity relationship studies indicate that in these compounds the ethoxy substituent is probably responsible for the improved activity. In addition, the DNA-binding potential of these compounds was also investigated by UV/vis, fluorescence, and circular dichroism spectroscopy.

An efficient metal-free, one-pot protocol was developed for the synthesis of variety benzimidazole and quinazolinones in moderate to good yields. This protocol proceeds via oxidation of benzylamine, resulting in in-situ aldehyde formation followed by the condensation with o-phenylenediamine and o-aminobenzamide to the corresponding N-heterocycles using a mild oxidant phenyliodonium diacetate (PIDA). We describe a new strategy for C–N bond cleavage and formation in the absence of transition-metal reagent or ligand under environmentally benign reaction conditions.

A facile method for the synthesis of a variety of β-carbolines and their natural products such as norharmane (2a), harmane (2b), eudistomins I, N, T, and U (6, 7, 9 and 10, respectively) has been successfully developed via a decorboxylative aromatization tool by employing N-chlorosuccinimide (NCS) as a mild and efficient reagent. Gratifyingly, this reagent system proceeds in a one-pot manner and converted all the tetrahydro-β-carboline acids into their corresponding decorboxylative aromatic products with good to excellent yields. Additionally, this system works well in the case of tetrahydro-β-carboline esters to produce their aromatic partners in high yields.

Chiral pyrrolidinyl-oxazolecarboxamides are synthesized and used as organocatalysts in the asymmetric Michael addition of ketones with nitroalkenes under solvent-free conditions.

The cytotoxicity of the products was investigated with some of the compounds being effective in selected human cancer cell lines.